Safety and Immunogenicity of a Live-attenuated Universal Flu Vaccine Followed by an Inactivated Universal Flu Vaccine

NCT03300050 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: CVIA 057 (1082166-1)
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 2

Brief Summary

The clinical study will evaluate safety and the immune response of a prime- boost regimen with a live attenuated influenza vaccine (LAIV) prime and an inactivated split influenza vaccine (IIV) boost with or without adjuvant.

Conditions

Influenza; Vaccine

Keywords

live attenuated influenza vaccine; inactivated influenza vaccine

Outcome Measures

Primary Outcomes (5)

• Number of Participants With Solicited Local Reactions Within 7 Days Following Each Vaccination

  Solicited adverse events were assessed by study staff for 60 minutes after each vaccination and and then by study participants daily for 7 days on a a diary card. Solicited local reactions included: * Post LAIV dose: nasal congestion, rhinorrhea; * Post IIV dose: pain, redness, swelling.

  7 days after each vaccination (Days 1-8 and Days 85-92)

• Number of Participants With Solicited General Reactions Within 7 Days Following Each Vaccination

  Solicited adverse events were assessed by study staff for 60 minutes after each vaccination and and then by study participants daily for 7 days on a a diary card. Solicited general reactions included: * abdominal pain * arthralgia * cough * diarrhea * fatigue * fever * headache * myalgia * nausea * shivering * sore throat * vomiting * wheezing

  7 days after each vaccination (Days 1-8 and Days 85-92)

• Number of Participants With Unsolicited Adverse Events Within 28 Days Following Any Vaccination

  Unsolicited adverse events (AEs) are any AEs reported spontaneously by the participant, observed by the study personnel during study visits or those identified during review of medical records or source documents, such as diary cards. Participants were asked to record any unsolicited symptoms or other illness description in their diary card during the 28 days after each vaccination. All AEs, including clinical laboratory test results, were assessed by a study clinician and the study subject (as applicable) to quantify severity using a protocol-defined grading system as mild (mild symptoms, easily tolerated, not interfering with daily activities), moderate (causing some interference with daily activity), or severe (severe symptoms that prevent normal every day activities). The investigator assessed the relationship between study vaccines and the occurrence of each AE using clinical judgment.

  28 days after each vaccination (Days 1 to 28 and Days 85 to 113)

• Number of Participants With Grade 2 or Higher Hematological and Biochemical Laboratory Abnormalities From Day 8 to Day 113

  Hematological and biochemical parameters assessed included hemoglobin, platelets, red blood cells, white blood cells (WBC), absolute neutrophil count (ANC), lymphocytes, monocytes, eosinophils, basophils, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, blood urea nitrogen (BUN) and BUN-to-creatinine ratio. Grading of laboratory parameters was based on the FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials as Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (severe), or Grade 4 (Potentially life-threatening). Grade 2 or higher: * BUN: \> 26 mg/dL * Creatinine: \> 1.7 mg/dL * ALT, AST: \> 2.5 × upper limit of normal (ULN) * Hemoglobin: \< 11.0 g/dL (females) or \< 12.5 g/dL (males) or change from baseline \> 1.5 g/dL * WBC: \> 15,000 cell/mm³ or \< 2,500 cell/mm³ * Lymphocytes: \< 750 cell/mm³ * ANC: \< 1,500 cell/mm³ * Eosinophils: \> 1,500 cell/mm³ * Platelets: \< 125,000 cell/mm³

  Days 8, 29, 85, 92, and 113

• Number of Participants With a Medically Attended Event (MAE), Laboratory-Confirmed Influenza-like Illness (LC-ILI), Potential Immune-mediated Disease (pIMD), or Serious Adverse Event (SAE) up to Day 113

  An MAE is an event for which the participant received medical attention such as hospitalization, an emergency room visit, or a visit to or from medical personnel. pIMDs are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune etiology. LC-ILI is defined as at least 1 systemic symptom (fever or myalgia) AND at least 1 respiratory symptom (cough or sore throat), confirmed by polymerase chain reaction (PCR) assay. An SAE is an AE that met any of the following: * Death * Life threatening * Required inpatient hospitalization or prolongation of existing hospitalization * Results in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions * Results in congenital anomaly/birth defect * An important medical event that may jeopardize the well-being of the subject or require medical or surgical intervention to prevent an above outcome.

  Through Day 113 (28 days post-dose 2)

Secondary Outcomes (68)

• Number of Participants With Any Grade 2 or Higher Hematological and Biochemical Laboratory Abnormalities From Month 9 to Month 15

  Month 9 (6 months post-dose 2) and Month 15 (12 months post-dose 2)

• Number of Participants With a Medically Attended Event (MAE), Laboratory-Confirmed Influenza-like Illness (LC-ILI), Potential Immune-mediated Disease (pIMD), or Serious Adverse Event (SAE) up to End of Study

  From first dose to end of study, 588 days (21 months; 18 months post-dose 2)

• Number of Participants in Groups 1, 2, and 3 With Detectable Influenza A Virus in Nasal and Oropharyngeal Swabs on Days 1 to 5

  Days 1 to 5

• Number of Participants in Groups 1, 2, and 3 With Viable Vaccine Virus in Cell Culture Through 5 Days Post-vaccination

  Days 1 to 5

• Percentage of Participants With Serum Anti-H1 Hemagglutinin Stalk Immunoglobulin G Antibody Seropositivity

  Baseline (pre-dose 1), Month 1 (28 days post-dose 1), Month 4 (28 days post-dose 2), Month 9 (6 months post-dose 2), and Month 15 (12 months post-dose 2)

Study Arms (5)

Group 1: cH8/1N1 LAIV and cH5/1N1 IIV + adjuvant

EXPERIMENTAL

Participants received 0.5 mL cH8/1N1 LAIV administered as 0.25 mL drops per nostril on Day 1 followed by 0.5 mL AS03-adjuvanted cH5/1N1 IIV administered as an intramuscular injection on Day 85.

Biological: cH8/1N1 LAIV; Biological: AS03-adjuvanted cH5/1N1 IIV

Group 2: cH8/1N1 LAIV and cH5/1N1 IIV

EXPERIMENTAL

Participants received 0.5 mL cH8/1N1 LAIV administered as 0.25 mL drops per nostril on Day 1 followed by 0.5 mL cH5/1N1 IIV administered as an intramuscular injection on Day 85.

Biological: cH8/1N1 LAIV; Biological: cH5/1N1 IIV

Group 3: Placebo

PLACEBO COMPARATOR

Participants received 0.5 mL of normal saline administered as 0.25 mL drops per nostril on Day 1 followed by 0.5 mL phosphate buffered saline (PBS) administered as an intramuscular injection on Day 85.

Biological: Normal saline; Biological: Phosphate buffered saline (PBS)

Group 4: cH8/1N1 IIV + adjuvant and cH5/1N1 IIV + adjuvant

EXPERIMENTAL

Participants received 0.5 mL AS03-adjuvanted cH8/1N1 IIV administered as an intramuscular injection on Day 1 followed by 0.5 mL AS03-adjuvanted cH5/1N1 IIV administered as an intramuscular injection on Day 85.

Biological: AS03-adjuvanted cH5/1N1 IIV; Biological: AS03-adjuvanted cH8/1N1 IIV

Group 5: Placebo

PLACEBO COMPARATOR

Participants received 0.5 mL PBS administered as an intramuscular injection on Day 1 followed by 0.5 mL PBS administered as an intramuscular injection on Day 85.

Biological: Phosphate buffered saline (PBS)

Interventions

cH8/1N1 LAIV BIOLOGICAL

Live-attenuated influenza virus vaccine (LAIV) expressing chimeric hemagglutinin (HA) with the H8 head and H1 stalk and neuraminidase (NA) subtype 1 (N1) (cH8/1N1): HA head, A/mallard/Sweden/24/2002 (H8N4); HA stalk, A/California/04/2009 (H1N1); NA, A/California/04/2009 (H1N1) containing the backbone of the cold-adapted/temperature sensitive of the Russian LAIV A/Leningrad/134/17/1957 (Len17 IDCDCRG46D). Administered intranasally as drops at a dose of 10⁷·⁵ (plus or minus ⁰·⁵) 50% egg infectious dose (EID50), formulated in a total volume of 0.5 mL sterile saline (0.25 mL per nostril).

Group 1: cH8/1N1 LAIV and cH5/1N1 IIV + adjuvant; Group 2: cH8/1N1 LAIV and cH5/1N1 IIV

AS03-adjuvanted cH5/1N1 IIV BIOLOGICAL

Chimeric H5 head with H1 stalk plus N1 (cH5/1N1) split virion inactivated influenza virus vaccine (IIV) plus AS03 adjuvant: HA head, A/Vietnam/1203/2004 (H5N1); HA stalk, A/California/04/2009 (H1N1); NA, A/California/04/2009 (H1N1). Administered intramuscularly at a dose of 15 μg of hemagglutinin in a volume of 0.5 mL of phosphate buffered saline (PBS).

Also known as: cH5/1N1 IIV + AS03 adjuvant

Group 1: cH8/1N1 LAIV and cH5/1N1 IIV + adjuvant; Group 4: cH8/1N1 IIV + adjuvant and cH5/1N1 IIV + adjuvant

cH5/1N1 IIV BIOLOGICAL

Chimeric H5 head with H1 stalk plus N1 (cH5/1N1) split virion inactivated influenza virus vaccine (IIV): HA head, A/Vietnam/1203/2004 (H5N1); HA stalk, A/California/04/2009 (H1N1); NA, A/California/04/2009 (H1N1). Administered intramuscularly at a dose of 15 μg of hemagglutinin in a volume of 0.5 mL of phosphate buffered saline (PBS).

Group 2: cH8/1N1 LAIV and cH5/1N1 IIV

AS03-adjuvanted cH8/1N1 IIV BIOLOGICAL

Chimeric H8 head with H1 stalk plus N1 (cH8/1N1) inactivated influenza vaccine plus AS03 adjuvant: HA head, A/mallard/Sweden/24/2002 (H8N4); HA stalk, A/California/04/2009 (H1N1); NA, A/California/04/2009 (H1N1). Administered intramuscularly at a dose of 15 μg of hemagglutinin in a volume of 0.5 mL of phosphate buffered saline (PBS).

Also known as: cH8/1N1 IIV + AS03 adjuvant

Group 4: cH8/1N1 IIV + adjuvant and cH5/1N1 IIV + adjuvant

Normal saline BIOLOGICAL

Administered intranasally as 0.25 mL nasal drops per nostril

Group 3: Placebo

Phosphate buffered saline (PBS) BIOLOGICAL

Administered intramuscularly as 0.5 mL injection

Group 3: Placebo; Group 5: Placebo

Eligibility Criteria

• Age: 18 Years - 39 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Able to understand planned study procedures and demonstrate comprehension of the protocol procedures and knowledge of study by passing a written examination prior to vaccination.
• In the opinion of the investigator, can and will comply with the requirements of the protocol (e.g., completion of the diary cards, return for follow-up visits).
• Written informed consent obtained from the subject prior to performance of any study specific procedure.
• Male or non-pregnant female between, and including, 18 and 39 years of age at the time of the first vaccination.
• Healthy subjects without acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality\*.
• Female subjects of non-childbearing potential may be enrolled in the study.
• Female subjects of childbearing potential must have a negative pregnancy test within 24 hours of vaccination.
• Female subjects of childbearing potential must have practiced adequate contraception for 30 days prior to first vaccination and agree to continue adequate contraception until 2 months after completion of the vaccination series (Month 5).
• Male subjects must be surgically sterile (e.g., vasectomy) or agree to practice adequate contraception from the first vaccination until 2 months after completion of the vaccination series (Month 5). Please refer to the glossary of terms for the definition of adequate contraception.

You may not qualify if:

• Use of any investigational or non-registered product (drug or vaccine) other than the study vaccines.
• Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe.
• Medically diagnosed deviated nasal septum or nasal obstruction.
• Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs within 6 months before the first dose.
• Administration of long-acting immune-modifying drugs (e.g., infliximab, rituximab) within 6 months before the first dose (Visit 03), or planned administration any time during the study period.
• Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting 30 days before the first dose (Visit 03) up to Month 15 (Visit 15)
• Persons who should be annually vaccinated against influenza who live with or care for persons at high risk for influenza-related complications.
• History of influenza vaccination within 6 months prior to study enrollment or unwillingness to forego seasonal influenza vaccination during the entire study period.
• History of vaccination with an investigational pandemic influenza vaccine other than an 2009 H1N1 Pandemic (H1N1pdm09) vaccine.
• Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination.
• Infection with human immunodeficiency virus regardless of clinical stage of immunodeficiency.
• History of current infection with hepatitis B virus or hepatitis C virus regardless of clinical presentation.
• History of or current autoimmune disease.
• Subjects diagnosed with excessive daytime sleepiness or narcolepsy; or history of narcolepsy in a subject's parent or sibling.
• History of Guillain-Barré syndrome.

Sponsors & Collaborators

• PATH: lead
• Icahn School of Medicine at Mount Sinai: collaborator
• Children's Hospital Medical Center, Cincinnati: collaborator
• Duke University: collaborator
• The Emmes Company, LLC: collaborator
• GlaxoSmithKline: collaborator

Study Sites (2)

Duke University

Durham, North Carolina, 27710, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Related Publications (3)

• Meade P, Strohmeier S, Bermudez-Gonzalez MC, Garcia-Sastre A, Palese P, Simon V, Krammer F. Antigenic Landscape Analysis of Individuals Vaccinated with a Universal Influenza Virus Vaccine Candidate Reveals Induction of Cross-Subtype Immunity. J Virol. 2023 Jan 31;97(1):e0107022. doi: 10.1128/jvi.01070-22. Epub 2022 Dec 19.

  PMID: 36533948 DERIVED

• Nachbagauer R, Feser J, Naficy A, Bernstein DI, Guptill J, Walter EB, Berlanda-Scorza F, Stadlbauer D, Wilson PC, Aydillo T, Behzadi MA, Bhavsar D, Bliss C, Capuano C, Carreno JM, Chromikova V, Claeys C, Coughlan L, Freyn AW, Gast C, Javier A, Jiang K, Mariottini C, McMahon M, McNeal M, Solorzano A, Strohmeier S, Sun W, Van der Wielen M, Innis BL, Garcia-Sastre A, Palese P, Krammer F. A chimeric hemagglutinin-based universal influenza virus vaccine approach induces broad and long-lasting immunity in a randomized, placebo-controlled phase I trial. Nat Med. 2021 Jan;27(1):106-114. doi: 10.1038/s41591-020-1118-7. Epub 2020 Dec 7.

  PMID: 33288923 DERIVED

• Bernstein DI, Guptill J, Naficy A, Nachbagauer R, Berlanda-Scorza F, Feser J, Wilson PC, Solorzano A, Van der Wielen M, Walter EB, Albrecht RA, Buschle KN, Chen YQ, Claeys C, Dickey M, Dugan HL, Ermler ME, Freeman D, Gao M, Gast C, Guthmiller JJ, Hai R, Henry C, Lan LY, McNeal M, Palm AE, Shaw DG, Stamper CT, Sun W, Sutton V, Tepora ME, Wahid R, Wenzel H, Wohlbold TJ, Innis BL, Garcia-Sastre A, Palese P, Krammer F. Immunogenicity of chimeric haemagglutinin-based, universal influenza virus vaccine candidates: interim results of a randomised, placebo-controlled, phase 1 clinical trial. Lancet Infect Dis. 2020 Jan;20(1):80-91. doi: 10.1016/S1473-3099(19)30393-7. Epub 2019 Oct 17.

  PMID: 31630990 DERIVED

MeSH Terms

Conditions

Influenza, Human

Interventions

AS03 adjuvant; Saline Solution

Condition Hierarchy (Ancestors)

Respiratory Tract Infections; Infections; Orthomyxoviridae Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Results Point of Contact

• Title: Jorge Flores, MD
• Organization: PATH

jeflores@path.org

(202) 822-0033

Study Officials

• David Bernstein, MD

  Children's Hospital Medical Center, Cincinnati

  PRINCIPAL INVESTIGATOR

• Jeffrey Guptill, MD

  Duke University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: An unblinded pharmacist will prepare Dose 1 and Dose 2. Participants and study staff will remain blinded to their exact treatment group but will be unblinded to their overall group allocation (inpatient or outpatient).
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Eligible enrolled subjects will be randomized to any of the treatment arms (LAIV-IIV, Groups 1, 2, and 3; or IIV-IIV, Groups 4 and 5) under one allocation sequence, stratified by site, to allow comparability between study groups, such as LAIV-IIV vs IIV-IIV regimens (Groups 1 vs 4). Groups 1-3 will be inpatient and receive either LAIV or placebo as nasal drops at Dose 1. Groups 4-5 ill be outpatient and receive either IIV or placebo as an injection at Dose 1.

Study Record Dates

• First Submitted: September 28, 2017
• First Posted: October 3, 2017
• Study Start: October 10, 2017
• Primary Completion: April 24, 2018
• Study Completion: August 9, 2019
• Last Updated: February 21, 2021
• Results First Posted: February 21, 2021

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)