Immune Responses to H5N1 Vaccine With and Without AS03 Adjuvant

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.

• H5N1 vaccine plus AS03 adjuvant (Biological): H5N1 influenza vaccine with AS03 at the 3.75 mcg dose level given 21 days apart.
• H5N1 vaccine without adjuvant (Biological): H5N1 influenza vaccine non- adjuvanted form at the 3.75 mcg dose level given 21 days apart.

Primary outcomes

• Flu Antibody Titers [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.

Sex: All, ages: 18 Years to 45 Years, accepts healthy volunteers

* 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.

Participant flow

Outcome results

• Flu Antibody Titers (Primary), Geometric mean, Titers: AS03 Adjuvanted 10.65 +/- 6.4; Unadjuvanted 10.35 +/- 2.24

Adverse events

Other adverse events by term

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• 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. PMID 19197383
• 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. PMID 11257408
• Results publication: 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. PMID 30302282

• John S Tsang, Ph.D., Principal investigator, National Institute of Allergy and Infectious Diseases (NIAID)