InfluenzaPhase 1/2NCT01578317
Immune Responses to H5N1 Vaccine With and Without AS03 Adjuvant
A Phase 1/2 study testing H5N1 vaccine plus AS03 adjuvant and H5N1 vaccine without adjuvant in people with Influenza, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in United States.
Trial summary
Background: Adjuvants are substances included in vaccines that stimulate the immune system and increase the body's response to the vaccine. The AS03 adjuvant is used in seasonal flu vaccines in Europe. However, it has not been fully tested in the United States. Read more about this study
- Who is it for?
- Ages 18 to 45 yearsHealthy volunteers can take part
- Conditions the study is for
- Influenza
- What is being tested?
- H5N1 vaccine plus AS03 adjuvant and H5N1 vaccine without adjuvant
- Type of treatment
- Vaccines
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 43 participants
- Where
- 1 siteUnited States
- Study dates
- 20 Mar 2012to 31 Jan 2016
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Healthy status confirmed by History, Physical Exam and blood work through the CHI Screening Protocol.
- Age 21 years to 45 years
- Able to comprehend the investigational nature of the protocol and provide informed consent
- Must be willing to use effective birth control for one month before, during and for two months after the last vaccination.
Who cannot join
- Severe allergies to eggs or their products, chicken proteins or to any component of the influenza antigen preparation.
- Recipient of AS03 vaccine at any time in the past
- Recipient of the seasonal influenza vaccine within the past 3 months.
- Prior severe reactions to vaccines, including influenza vaccines (e.g. anaphylaxis, angioedema or urticaria)
- Participation on any blood collection or blood donation procedure during study that will bring the total blood draw >550ml over 8 weeks
- Current pregnancy (women of child bearing potential must have a negative serum pregnancy test done on screening within 1 week of protocol accrual)
Show all 14Show fewer
- Currently breast-feeding
- History of Guillain Barre syndrome
- Acute illness with patient reported temperature of 38 (Infinite)C or greater within 3 days prior to the proposed time of administration.
- Any history or presence of serious illness, bleeding disorders or autoimmune disorders, or planned surgeries.
- Weight less than 50 kg (110 pounds)
- History of hepatitis or liver disease.
- Subjects receiving immunosuppressive therapy.
- Presence of HLA DQB1*06:02, the narcolepsy risk associated allele.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Characterization of Innate Immune Responses to AS03 Adjuvanted H5N1 Vaccine Compared to Non-adjuvanted H5N1 Vaccine
Background:
- Adjuvants are substances included in vaccines that stimulate the immune system and increase the body's response to the vaccine. The AS03 adjuvant is used in seasonal flu vaccines in Europe. However, it has not been fully tested in the United States. Researchers want to test the immune responses of people who receive a bird flu vaccine with or without AS03 to better understand how the adjuvant works. This information may help develop better flu vaccines.
Read more
Objectives:
- To compare the healthy immune system responses to bird flu vaccine with or without the AS03 adjuvant.
Eligibility:
- Healthy volunteers between 18 and 45 years of age.
Design:
- Participants will be screened with a physical exam and medical history.
- Participants will be assigned to one of two groups. Each group will have an initial vaccine, followed by a booster vaccine 21 days later. Both vaccinations will use the same type of vaccine. One group will have the vaccine with AS03; the other group will have the vaccine without it.
- All participants will have two 36-hour inpatient stays to receive the vaccine. Each stay will involve the vaccination, followed by regular and frequent blood draws. Participants will be monitored for any signs or symptoms that may be caused by the vaccine.
- Additional blood samples will be collected 7, 28, 42, and 100 days after the initial vaccination.
Read the detailed description
Adjuvants have been in use for many decades to enhance the effects of vaccines on the host immune system, yet we know very little on how they actually work. Better understanding of the mechanism by which adjuvants activate the immune system will enable us to develop better and safer vaccines as well as a broad range of immune interventions to a wide spectrum of diseases including cancer and autoimmunity.
In the current study we propose to study the effect of AS03 adjuvant on the innate/early immune response to H5N1, avian flu, a potentially lethal disease that most subjects are assumed to be naive to AS03 is an adjuvant oil in water emulsion containing DL-alpha-tocopherol, squalene and the non-ionic detergent Tween 80 that has been widely used as an adjuvant to flu vaccines produced by GlaxoSmithKline(GSK).
We therefore propose to randomize up to 60 healthy volunteers into two intervention arms (25 volunteers in each arm with up to 10 total replacements in the event a volunteer does not return for the first vaccine). The first arm will receive a vaccine containing H5N1 with AS03 adjuvant, the second arm will receive H5N1 without AS03 adjuvant. Both arms will receive primary and booster vaccination followed by repeated blood sampling to evaluate the immune responses. We will apply high throughput analytic techniques and use systems biology methods to integrate the collected data and draw a description of the immune system response with and without the adjuvant.
The primary objective is to compare multiplex immune response signatures following two (primary and a boost) vaccinations with the GSK AS03 adjuvanted H5N1 influenza vaccine, or the non-adjuvanted form of the H5N1 influenza vaccine, at the 3.75 mcg dose and given 21 days apart and identify differences in very early innate immune responses. These immune signatures will also be correlated with the clinical observations especially safety related local and systemic events.
- Conditions
- Influenza
- Being tested
- H5N1 vaccine plus AS03 adjuvant, H5N1 vaccine without adjuvant
- Keywords
- H5N1 Vaccine, H5N1 Immunization, AS03 Adjuvant, Biologic Sample Collection, Laboratory Research Specimens, Healthy Volunteer, HV
- Medical subject headings
- Influenza, Human
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
H5N1 vaccine plus AS03 adjuvantBiological
H5N1 influenza vaccine with AS03 at the 3.75 mcg dose level given 21 days apart.
H5N1 vaccine without adjuvantBiological
H5N1 influenza vaccine non- adjuvanted form at the 3.75 mcg dose level given 21 days apart.
| Study group | Role | What they receive |
|---|---|---|
| AS03 adjuvanted | Experimental | Adminsitered day 1, booster at Day 21 Receives: Biological: H5N1 vaccine plus AS03 adjuvant |
| unadjuvanted | Experimental | Administer day 1 and booster at Day 21 Receives: Biological: H5N1 vaccine without adjuvant |
What is being measured
The primary outcome is the main question the study is designed to answer.
Flu Antibody Titers
Flu Antibody titers at days 0, 21, 42, 100. Antibody-neutralization titers by microneutralization were measured against five different H5N1 virus strains (i.e., A/Vietnam/1194/2004 (clade 1), A/Indonesia/5/2005 (clade 2.1), A/Turkey/15/2006 (clade 2.2), A/Egypt/3072/2010 (clade 2.2), and A/Anhui/1/2005 (clade 2.3.4)) at day 0 (prevaccination), day 21 (post first vaccination), day 42 (post second vaccination) and day 100 postvaccination for AS03-adjuvanted group and unadjuvanted group. Sera were tested at an initial dilution of 1:20, and those that were negative (<1:20) were assigned a titer of 10.
Measured: Days 0, 21, 42, and 100
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Apr 2012 (estimated)
- Study start20 Mar 2012
- Primary completion31 Jan 2016
- Study completion31 Jan 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for InfluenzaStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 43 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- John S Tsang, Ph.D., Principal investigator, National Institute of Allergy and Infectious Diseases (NIAID)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01578317
- Sponsor's protocol ID
- 120103
- Other IDs
- 12-I-0103
- Status last verified
- Sep 2018
- First submitted
- 4 Apr 2012
- Last updated
- 26 Feb 2019
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
Publications
Atmar RL, Keitel WA, Patel SM, Katz JM, She D, El Sahly H, Pompey J, Cate TR, Couch RB. Safety and immunogenicity of nonadjuvanted and MF59-adjuvanted influenza A/H9N2 vaccine preparations. Clin Infect Dis. 2006 Nov 1;43(9):1135-42. doi: 10.1086/508174. Epub 2006 Sep 25.
PubMed 17029131Banzhoff A, Gasparini R, Laghi-Pasini F, Staniscia T, Durando P, Montomoli E, Capecchi PL, di Giovanni P, Sticchi L, Gentile C, Hilbert A, Brauer V, Tilman S, Podda A. MF59-adjuvanted H5N1 vaccine induces immunologic memory and heterotypic antibody responses in non-elderly and elderly adults. PLoS One. 2009;4(2):e4384. doi: 10.1371/journal.pone.0004384. Epub 2009 Feb 6.
PubMed 19197383Podda A. The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine. Vaccine. 2001 Mar 21;19(17-19):2673-80. doi: 10.1016/s0264-410x(00)00499-0.
PubMed 11257408Khurana S, Coyle EM, Manischewitz J, King LR, Gao J, Germain RN, Schwartzberg PL, Tsang JS, Golding H; and the CHI Consortium. AS03-adjuvanted H5N1 vaccine promotes antibody diversity and affinity maturation, NAI titers, cross-clade H5N1 neutralization, but not H1N1 cross-subtype neutralization. NPJ Vaccines. 2018 Oct 1;3:40. doi: 10.1038/s41541-018-0076-2. eCollection 2018.
PubMed 30302282
Study at a glance
From the registry record, last updated by the sponsor on 26 Feb 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Characterization of Innate Immune Responses to AS03 Adjuvanted H5N1 Vaccine Compared to Non-adjuvanted H5N1 Vaccine
- ClinicalTrials.gov ID
- NCT01578317
- Acronym / sponsor ID
- 120103
- Conditions
- Influenza
- Keywords
- H5N1 Vaccine, H5N1 Immunization, AS03 Adjuvant, Biologic Sample Collection, Laboratory Research Specimens, Healthy Volunteer, HV
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 43 participants (actual)
- Lead sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
- Study start
- 20 Mar 2012
- Primary completion
- 31 Jan 2016 (actual)
- Study completion
- 31 Jan 2016 (actual)
- First posted
- 16 Apr 2012 (estimated)
- Results
- Posted 26 Feb 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background:
- Adjuvants are substances included in vaccines that stimulate the immune system and increase the body's response to the vaccine. The AS03 adjuvant is used in seasonal flu vaccines in Europe. However, it has not been fully tested in the United States. Researchers want to test the immune responses of people who receive a bird flu vaccine with or without AS03 to better understand how the adjuvant works. This information may help develop better flu vaccines.
Objectives:
- To compare the healthy immune system responses to bird flu vaccine with or without the AS03 adjuvant.
Eligibility:
- Healthy volunteers between 18 and 45 years of age.
Design:
- Participants will be screened with a physical exam and medical history.
- Participants will be assigned to one of two groups. Each group will have an initial vaccine, followed by a booster vaccine 21 days later. Both vaccinations will use the same type of vaccine. One group will have the vaccine with AS03; the other group will have the vaccine without it.
- All participants will have two 36-hour inpatient stays to receive the vaccine. Each stay will involve the vaccination, followed by regular and frequent blood draws. Participants will be monitored for any signs or symptoms that may be caused by the vaccine.
- Additional blood samples will be collected 7, 28, 42, and 100 days after the initial vaccination.
Detailed description
Adjuvants have been in use for many decades to enhance the effects of vaccines on the host immune system, yet we know very little on how they actually work. Better understanding of the mechanism by which adjuvants activate the immune system will enable us to develop better and safer vaccines as well as a broad range of immune interventions to a wide spectrum of diseases including cancer and autoimmunity.
In the current study we propose to study the effect of AS03 adjuvant on the innate/early immune response to H5N1, avian flu, a potentially lethal disease that most subjects are assumed to be naive to AS03 is an adjuvant oil in water emulsion containing DL-alpha-tocopherol, squalene and the non-ionic detergent Tween 80 that has been widely used as an adjuvant to flu vaccines produced by GlaxoSmithKline(GSK).
We therefore propose to randomize up to 60 healthy volunteers into two intervention arms (25 volunteers in each arm with up to 10 total replacements in the event a volunteer does not return for the first vaccine). The first arm will receive a vaccine containing H5N1 with AS03 adjuvant, the second arm will receive H5N1 without AS03 adjuvant. Both arms will receive primary and booster vaccination followed by repeated blood sampling to evaluate the immune responses. We will apply high throughput analytic techniques and use systems biology methods to integrate the collected data and draw a description of the immune system response with and without the adjuvant.
The primary objective is to compare multiplex immune response signatures following two (primary and a boost) vaccinations with the GSK AS03 adjuvanted H5N1 influenza vaccine, or the non-adjuvanted form of the H5N1 influenza vaccine, at the 3.75 mcg dose and given 21 days apart and identify differences in very early innate immune responses. These immune signatures will also be correlated with the clinical observations especially safety related local and systemic events.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| AS03 adjuvanted | Experimental | Biological: H5N1 vaccine plus AS03 adjuvantAdminsitered day 1, booster at Day 21 |
| unadjuvanted | Experimental | Biological: H5N1 vaccine without adjuvantAdminister day 1 and booster at Day 21 |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
Key exclusion criteria (14 listed)
- Severe allergies to eggs or their products, chicken proteins or to any component of the influenza antigen preparation.
- Recipient of AS03 vaccine at any time in the past
- Recipient of the seasonal influenza vaccine within the past 3 months.
- Prior severe reactions to vaccines, including influenza vaccines (e.g. anaphylaxis, angioedema or urticaria)
- Participation on any blood collection or blood donation procedure during study that will bring the total blood draw >550ml over 8 weeks
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| H5N1 vaccine plus AS03 adjuvantH5N1 influenza vaccine with AS03 at the 3.75 mcg dose level given 21 days apart. | Biological | AS03 adjuvanted |
| H5N1 vaccine without adjuvantH5N1 influenza vaccine non- adjuvanted form at the 3.75 mcg dose level given 21 days apart. | Biological | unadjuvanted |
Primary outcome
Flu Antibody Titers
Time frame: Days 0, 21, 42, and 100
Flu Antibody titers at days 0, 21, 42, 100. Antibody-neutralization titers by microneutralization were measured against five different H5N1 virus strains (i.e., A/Vietnam/1194/2004 (clade 1), A/Indonesia/5/2005 (clade 2.1), A/Turkey/15/2006 (clade 2.2), A/Egypt/3072/2010 (clade 2.2), and A/Anhui/1/2005 (clade 2.3.4)) at day 0 (prevaccination), day 21 (post first vaccination), day 42 (post second vaccination) and day 100 postvaccination for AS03-adjuvanted group and unadjuvanted group. Sera were tested at an initial dilution of 1:20, and those that were negative (<1:20) were assigned a titer of 10.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Feb 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 17029131Atmar RL, Keitel WA, Patel SM, Katz JM, She D, El Sahly H, Pompey J, Cate TR, Couch RB. Safety and immunogenicity of nonadjuvanted and MF59-adjuvanted influenza A/H9N2 vaccine preparations. Clin Infect Dis. 2006 Nov 1;43(9):1135-42. doi: 10.1086/508174. Epub 2006 Sep 25.
- Background: PubMed 19197383Banzhoff A, Gasparini R, Laghi-Pasini F, Staniscia T, Durando P, Montomoli E, Capecchi PL, di Giovanni P, Sticchi L, Gentile C, Hilbert A, Brauer V, Tilman S, Podda A. MF59-adjuvanted H5N1 vaccine induces immunologic memory and heterotypic antibody responses in non-elderly and elderly adults. PLoS One. 2009;4(2):e4384. doi: 10.1371/journal.pone.0004384. Epub 2009 Feb 6.
- Background: PubMed 11257408Podda A. The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine. Vaccine. 2001 Mar 21;19(17-19):2673-80. doi: 10.1016/s0264-410x(00)00499-0.
- Results publication: PubMed 30302282Khurana S, Coyle EM, Manischewitz J, King LR, Gao J, Germain RN, Schwartzberg PL, Tsang JS, Golding H; and the CHI Consortium. AS03-adjuvanted H5N1 vaccine promotes antibody diversity and affinity maturation, NAI titers, cross-clade H5N1 neutralization, but not H1N1 cross-subtype neutralization. NPJ Vaccines. 2018 Oct 1;3:40. doi: 10.1038/s41541-018-0076-2. eCollection 2018.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
John S Tsang, Ph.D. principal investigator
National Institute of Allergy and Infectious Diseases (NIAID)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing H5N1 vaccine plus AS03 adjuvant and H5N1 vaccine without adjuvant in people with Influenza, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 26 Feb 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 26 Feb 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Flu Antibody Titers (time frame: Days 0, 21, 42, and 100). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01578317, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Feb 2019.