Reactogenicity, Safety, and Immunogenicity of a Live Monovalent H5N2 Influenza Vaccine

Reactogenicity, Safety and Immunogenicity of a Live Monovalent A/17/Turkey/Turkey/05/133 (H5N2) Influenza Vaccine

To evaluate the safety profile of two intranasal doses of LAIV A/17/turkey/Turkey/05/133 (H5N2) in healthy adults.

Study Overview

• Status: Completed
• Conditions: Influenza
• Intervention / Treatment: Biological: LAIV H5N2; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• Russian Federation
  • St. Petersburg, Russian Federation, 197376
    • Research Institute of Influenza

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 49 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Legal male or female adult 18 through 49 years of age at the enrollment visit.
• Literate and willing to provide written informed consent.
• Free of obvious health problems, as established by the medical history and screening evaluations, including physical examination.
• Capable and willing to complete diary cards and willing to return for all follow-up visits
• Willing to comply with the rules of the isolation unit (including willing and able to take oseltamivir influenza antiviral medication, should that be recommended by a study physician).
• For females, willing to take reliable birth control measures throughout the entire period of participation in the study.

Exclusion Criteria:

• Participation in another clinical trial involving any therapy within the previous three months or planned enrollment in such a trial during the period of this study.
• Receipt of any non-study vaccine within four weeks prior to enrollment or refusal to postpone receipt of such vaccines until four weeks after study completion.
• Practice of nasal irrigation on a regular basis within the past six months or has engaged in nasal irrigation within two weeks prior to enrollment.
• Recent history of frequent nose bleeds (>5 within the past year).
• Clinically relevant abnormal paranasal anatomy.
• Recent history (within the past month) of rhino or sinus surgery, or surgery for any traumatic injury of the nose.
• Current or recent (within two weeks of enrollment) acute respiratory illness with or without fever.
• Other acute illness at the time of study enrollment.
• Receipt of immune globulin or other blood products within three months prior to study enrollment or planned receipt of such products during the period of subject participation in the study.
• Chronic administration (defined as more than 14 consecutively-prescribed days) of immunosuppressants or other immune-modulating therapy within six months prior to study enrollment. (For corticosteroids, this means prednisone or equivalent, 0.5 mg per kg per day; topical steroids are allowed, exclusive of nasal.)
• Participation in any previous trial of any H5 or H7 containing influenza vaccine.
• History of asthma.
• Hypersensitivity after previous administration of any influenza vaccine.
• History of wheezing after past receipt of any live influenza vaccine.
• Other adverse event (AE) following immunization, at least possibly related to previous receipt of any influenza vaccine.
• Suspected or known hypersensitivity to any of the study vaccine components, including chicken or egg protein.
• Seasonal (autumnal) hypersensitivity to the natural environment.
• Acute or chronic clinically significant pulmonary, cardiovascular, hepatic, metabolic, neurologic, psychiatric or renal functional abnormality, as determined by medical history, physical examination or clinical laboratory screening tests, which in the opinion of the investigator, might interfere with the study objectives. Subjects with physical examination findings or clinical laboratory screening results which would be graded 2 or higher on the AE severity grading scale (see Attachments) will be excluded from entry into the study and will be excluded from receipt of dose two of study vaccine or placebo.
• History of leukemia or any other blood or solid organ cancer.
• History of thrombocytopenic purpura or known bleeding disorder.
• History of seizures.
• Known or suspected immunosuppressive or immunodeficient condition of any kind, including HIV infection.
• Known chronic hepatitis B (HBV) or hepatitis C (HCV) infection.
• Known tuberculosis infection or evidence of previous tuberculosis exposure.
• History of chronic alcohol abuse and/or illegal drug use.
• Claustrophobia or sociophobia.
• Pregnancy or lactation. (A negative pregnancy test will be required before administration of study vaccine or placebo for all women of childbearing potential.)
• Any condition that, in the opinion of the investigator, would increase the health risk to the subject if he/she participates in the study or would interfere with the evaluation of the study objectives

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LAIV H5N2; Two doses of live monovalent influenza vaccine A/17/turkey/Turkey/05/133 ( live monovalent (LAIV H5N2) given intranasally	Biological: LAIV H5N2; 2 doses provided intranasally; Other Names: A/17/turkey/Turkey/05/133(H5N2)live influenza vaccine
Placebo Comparator: Placebo; two doses of placebo solution intranasal	Other: Placebo; 2 doses of placebo provided intranasally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events by Severity	Occurrence of participants with adverse events associated with intranasal administration, by worst grade of severity	6 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number/Percentage of Subjects With Seroconversion for Serum Hemagglutination Inhibition (HAI)	Defined as a four-fold or greater antibody rise in titer from pre-vaccination level. HAI = hemagglutination-inhibition, conducted using World Health Organization (WHO)-recommended protocols.	28 days (Dose 1) and 56 days (Dose 2)
Number/Percentage of Subjects With Serum Neutralizing Antibodies	Defined as a four-fold or greater antibody rise in titer from pre-vaccination level. Measured by microneutralization assay in Madin-Darby canine kidney cells (MDCK).	28 days (Dose 1) and 56 days (Dose 2)
Number/Percentage of Subjects With Seroconversion for Serum Immunoglobulin A (IgA)	IgA = immunoglobulin class A antibodies Determined using ELISA using whole purified H5N2	28 days (Dose 1) and 56 days (Dose 2)
Number/Percentage of Subjects With Seroconversion for Serum Immunoglobulin G (IgG)	Determined using ELISA using whole purified H5N2.	28 days (Dose 1) and 56 days (Dose 2)
Number/Percentage of Subjects With Seroconversion for Secretory IgA	IgA antibodies from the nasal mucosa detected in nasal wick specimens. Determined using ELISA using whole purified H5N2	28 days (Dose 1) and 56 days (Dose 2)
Number/Percentage of Subjects With Seroconversion for IgA in Saliva	IgA = Immunoglobulin Class A antibodies. Determined using ELISA using whole purified H5N2.	28 days (Dose 1) and 56 days (Dose 2)
Number/Percentage of Vaccinated Participants Shedding Influenza Virus After First Dose	Nasal swabs were collected and used for Reverse transcription polymerase chain reaction (rRTPCR) assays to detect shedding of influenza virus for days 1-6 of the study.	6 days post-vaccination
Number/Percentage of Vaccinated Participants Shedding Influenza Virus After Second Dose	Nasal swabs were collected and used for Reverse transcription polymerase chain reaction (rRTPCR) assays to detect shedding of influenza virus for days 29-34 of the study (6 days after the second vaccination).	6 days post-vaccination
Geometric Mean Titers for Serum HAI Antibodies	Geometric mean titers for serum hemagglutination inhibition antibodies	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Geometric Mean Titers (GMT) for Serum Neutralizing Antibodies	Geometric mean titers for serum neutralizing antibodies measured by microneutralization assay	0 days, 28 days (Dose 1) and 56 days (Dose 2)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number/Percentage of Subjects Exhibiting CD8+ IFNγ+ Responses	Nasal swabs from days 1, 2, 3, 5, and 7 after the first vaccination and on days 1 and 3, corresponding to days 29 and 31,respectively, after the second dose were tested for viral shedding by inoculation in 10- to 11-day-old embryonated chicken eggs (ECE) followed by incubation at 32◦C for 72 h. Influenza virus was detected by standard hemagglutination test with 1% chicken red blood cells. An increase in the number of antigenic-specific T cells greater than 3 standard deviations over the mean placebo values was regarded as a positive T cell response.	28 days (Dose 1) and 56 days (Dose 2)
Number/Percentage of Subjects Exhibiting CD4+ IFNγ+ Responses	Nasal swabs from days 1, 2, 3, 5, and 7 after the first vaccination and on days 1 and 3, corresponding to days 29 and 31,respectively, after the second dose were tested for viral shedding by inoculation in 10- to 11-day-old ECE followed by incubation at 32◦C for 72 h. Influenza virus was detected by standard hemagglutination test with 1% chicken red blood cells. An increase in the number of antigenic-specific T cells greater than 3 standard deviations over the mean placebo values was regarded as a positive T cell response.	28 days (Dose 1) and 56 days (Dose 2)
Number/Percentage of Subjects Exhibiting CD8+ IFNγ+ Effector Memory T Cell Responses	Nasal swabs from days 1, 2, 3, 5, and 7 after the first vaccination and on days 1 and 3, corresponding to days 29 and 31,respectively, after the second dose were tested for viral shedding by inoculation in 10- to 11-day-old ECE followed by incubation at 32◦C for 72 h. Influenza virus was detected by standard hemagglutination test with 1% chicken red blood cells. An increase in the number of antigenic-specific T cells greater than 3SD over the mean placebo values was regarded as a positive T cell response.	28 days (Dose 1) and 56 days (Dose 2)
Number/Percentage of Subjects Exhibiting CD4+ IFNγ+ Central Memory T Cell Responses	Nasal swabs from days 1, 2, 3, 5, and 7 after the first vaccination and on days 1 and 3, corresponding to days 29 and 31,respectively, after the second dose were tested for viral shedding by inoculation in 10- to 11-day-old ECE followed by incubation at 32◦C for 72 h. Influenza virus was detected by standard hemagglutination test with 1% chicken red blood cells. An increase in the number of antigenic-specific T cells greater than 3SD over the mean placebo values was regarded as a positive T cell response.	28 days (Dose 1) and 56 days (Dose 2)
Number/Percentage of Subjects Exhibiting CD4+ IFNγ+ Effector Memory T Cell Responses	Nasal swabs from days 1, 2, 3, 5, and 7 after the first vaccination and on days 1 and 3, corresponding to days 29 and 31,respectively, after the second dose were tested for viral shedding by inoculation in 10- to 11-day-old ECE followed by incubation at 32◦C for 72 h. Influenza virus was detected by standard hemagglutination test with 1% chicken red blood cells. An increase in the number of antigenic-specific T cells greater than 3SD over the mean placebo values was regarded as a positive T cell response.	28 days (Dose 1) and 56 days (Dose 2)
Number/Percentage of Subjects Exhibiting CD8+ IFNγ+ Central Memory T Cell Responses	Nasal swabs from days 1, 2, 3, 5, and 7 after the first vaccination and on days 1 and 3, corresponding to days 29 and 31,respectively, after the second dose were tested for viral shedding by inoculation in 10- to 11-day-old ECE followed by incubation at 32◦C for 72 h. Influenza virus was detected by standard hemagglutination test with 1% chicken red blood cells. An increase in the number of antigenic-specific T cells greater than 3SD over the mean placebo values was regarded as a positive T cell response.	28 days (Dose 1) and 56 days (Dose 2)

Collaborators and Investigators

• Sponsor: PATH
• Collaborators: Institute of Experimental Medicine, Russia; Microgen

Publications and helpful links

General Publications

• Kiseleva I, Dubrovina I, Fedorova E, Larionova N, Isakova-Sivak I, Bazhenova E, Pisareva M, Kuznetsova V, Flores J, Rudenko L. Genetic stability of live attenuated vaccines against potentially pandemic influenza viruses. Vaccine. 2015 Dec 8;33(49):7008-14. doi: 10.1016/j.vaccine.2015.09.050. Epub 2015 Oct 2.
• Rudenko L, Kiseleva I, Stukova M, Erofeeva M, Naykhin A, Donina S, Larionova N, Pisareva M, Krivitskaya V, Flores J; Russian LAIV Trial Study Group. Clinical testing of pre-pandemic live attenuated A/H5N2 influenza candidate vaccine in adult volunteers: results from a placebo-controlled, randomized double-blind phase I study. Vaccine. 2015 Sep 22;33(39):5110-7. doi: 10.1016/j.vaccine.2015.08.019. Epub 2015 Aug 19.

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): January 1, 2013
• Study Completion (Actual): January 1, 2013

Study Registration Dates

• First Submitted: October 26, 2012
• First Submitted That Met QC Criteria: October 30, 2012
• First Posted (Estimate): November 1, 2012

Study Record Updates

• Last Update Posted (Actual): November 28, 2018
• Last Update Submitted That Met QC Criteria: November 26, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: vaccine; influenza; pandemic
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: LAIV-H5N2-01