Clinical trial NCT01578317: Immune Responses to H5N1 Vaccine With and Without AS03 Adjuvant
Official title: Characterization of Innate Immune Responses to AS03 Adjuvanted H5N1 Vaccine Compared to Non-adjuvanted H5N1 Vaccine
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Influenza
Keywords: H5N1 Vaccine
H5N1 Immunization
AS03 Adjuvant
Biologic Sample Collection
Laboratory Research Specimens
Healthy Volunteer
HV
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2012-04-16
Enrollment: 43
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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. 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.

Eligibility criteria: * INCLUSION CRITERIA:

  1. Healthy status confirmed by History, Physical Exam and blood work through the CHI Screening Protocol.
  2. Age 21 years to 45 years
  3. Able to comprehend the investigational nature of the protocol and provide informed consent
  4. Must be willing to use effective birth control for one month before, during and for two months after the last vaccination.

EXCLUSION CRITERIA:

1. Severe allergies to eggs or their products, chicken proteins or to any component of the influenza antigen preparation.
2. Recipient of AS03 vaccine at any time in the past
3. Recipient of the seasonal influenza vaccine within the past 3 months.
4. Prior severe reactions to vaccines, including influenza vaccines (e.g. anaphylaxis, angioedema or urticaria)
5. Participation on any blood collection or blood donation procedure during study that will bring the total blood draw \>550ml over 8 weeks
6. Current pregnancy (women of child bearing potential must have a negative serum pregnancy test done on screening within 1 week of protocol accrual)
7. Currently breast-feeding
8. History of Guillain Barre syndrome
9. Acute illness with patient reported temperature of 38 (Infinite)C or greater within 3 days prior to the proposed time of administration.
10. Any history or presence of serious illness, bleeding disorders or autoimmune disorders, or planned surgeries.
11. Weight less than 50 kg (110 pounds)
12. History of hepatitis or liver disease.
13. Subjects receiving immunosuppressive therapy.
14. Presence of HLA DQB1\*06:02, the narcolepsy risk associated allele.

Primary outcomes:
measure: Flu Antibody Titers
timeFrame: Days 0, 21, 42, and 100
Secondary outcomes:
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
name: John S Tsang, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Banzhoff 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.
citation: Podda 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.
citation: Khurana 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.