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

• ClinicalTrials.gov Identifier: NCT01719783
• Recruitment Status: Completed
• First Posted: November 1, 2012
• Results First Posted: November 28, 2018
• Last Update Posted: November 28, 2018
• Sponsor: PATH
• Collaborators: Microgen; Institute of Experimental Medicine, Russia
• Information provided by (Responsible Party): PATH

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Influenza	Biological: LAIV H5N2; Other: Placebo	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Reactogenicity, Safety and Immunogenicity of a Live Monovalent A/17/Turkey/Turkey/05/133 (H5N2) Influenza Vaccine
• Study Start Date: September 2012
• Actual Primary Completion Date: January 2013
• Actual Study Completion Date: January 2013

Arms and Interventions

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 Name: 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

Outcome Measures

Primary Outcome Measures :

1. Adverse Events by Severity [ Time Frame: 6 days ]
   Occurrence of participants with adverse events associated with intranasal administration, by worst grade of severity

Secondary Outcome Measures :

1. Number/Percentage of Subjects With Seroconversion for Serum Hemagglutination Inhibition (HAI) [ Time Frame: 28 days (Dose 1) and 56 days (Dose 2) ]

   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.

2. Number/Percentage of Subjects With Serum Neutralizing Antibodies [ Time Frame: 28 days (Dose 1) and 56 days (Dose 2) ]

   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).

3. Number/Percentage of Subjects With Seroconversion for Serum Immunoglobulin A (IgA) [ Time Frame: 28 days (Dose 1) and 56 days (Dose 2) ]
   IgA = immunoglobulin class A antibodies Determined using ELISA using whole purified H5N2
4. Number/Percentage of Subjects With Seroconversion for Serum Immunoglobulin G (IgG) [ Time Frame: 28 days (Dose 1) and 56 days (Dose 2) ]
   Determined using ELISA using whole purified H5N2.
5. Number/Percentage of Subjects With Seroconversion for Secretory IgA [ Time Frame: 28 days (Dose 1) and 56 days (Dose 2) ]
   IgA antibodies from the nasal mucosa detected in nasal wick specimens. Determined using ELISA using whole purified H5N2
6. Number/Percentage of Subjects With Seroconversion for IgA in Saliva [ Time Frame: 28 days (Dose 1) and 56 days (Dose 2) ]
   IgA = Immunoglobulin Class A antibodies. Determined using ELISA using whole purified H5N2.
7. Number/Percentage of Vaccinated Participants Shedding Influenza Virus After First Dose [ Time Frame: 6 days post-vaccination ]
   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.
8. Number/Percentage of Vaccinated Participants Shedding Influenza Virus After Second Dose [ Time Frame: 6 days post-vaccination ]
   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).
9. Geometric Mean Titers for Serum HAI Antibodies [ Time Frame: 0 days, 28 days (Dose 1) and 56 days (Dose 2) ]
   Geometric mean titers for serum hemagglutination inhibition antibodies
10. Geometric Mean Titers (GMT) for Serum Neutralizing Antibodies [ Time Frame: 0 days, 28 days (Dose 1) and 56 days (Dose 2) ]
    Geometric mean titers for serum neutralizing antibodies measured by microneutralization assay

Other Outcome Measures:

1. Number/Percentage of Subjects Exhibiting CD8+ IFNγ+ Responses [ Time Frame: 28 days (Dose 1) and 56 days (Dose 2) ]

   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.

2. Number/Percentage of Subjects Exhibiting CD4+ IFNγ+ Responses [ Time Frame: 28 days (Dose 1) and 56 days (Dose 2) ]

   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.

3. Number/Percentage of Subjects Exhibiting CD8+ IFNγ+ Effector Memory T Cell Responses [ Time Frame: 28 days (Dose 1) and 56 days (Dose 2) ]

   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.

4. Number/Percentage of Subjects Exhibiting CD4+ IFNγ+ Central Memory T Cell Responses [ Time Frame: 28 days (Dose 1) and 56 days (Dose 2) ]

   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.

5. Number/Percentage of Subjects Exhibiting CD4+ IFNγ+ Effector Memory T Cell Responses [ Time Frame: 28 days (Dose 1) and 56 days (Dose 2) ]

   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.

6. Number/Percentage of Subjects Exhibiting CD8+ IFNγ+ Central Memory T Cell Responses [ Time Frame: 28 days (Dose 1) and 56 days (Dose 2) ]

   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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

Russian Federation

Research Institute of Influenza

St. Petersburg, Russian Federation, 197376

Sponsors and Collaborators

PATH

Microgen

Institute of Experimental Medicine, Russia

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: PATH
• ClinicalTrials.gov Identifier: NCT01719783
• Other Study ID Numbers: LAIV-H5N2-01
• First Posted: November 1, 2012
• Results First Posted: November 28, 2018
• Last Update Posted: November 28, 2018
• Last Verified: November 2018

Keywords provided by PATH:

influenza; vaccine; pandemic

Additional relevant MeSH terms:

Influenza, Human; Respiratory Tract Infections; Infections; Orthomyxoviridae Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Vaccines; Immunologic Factors; Physiological Effects of Drugs