Safety and cross-reactive immunogenicity of candidate AS03-adjuvanted prepandemic H5N1 influenza vaccines: a randomized controlled phase 1/2 trial in adults.
BACKGROUND
The tocopherol-based oil-in-water emulsion adjuvant system family (AS03) improves antigen sparing with split-virion H5N1 influenza vaccines, representing an important development for pandemic preparedness. In this phase 1/2 randomized, controlled, observer-blinded study in 680 adults, we assessed the immunogenicity and safety of A/Indonesia/5/05 H5N1 (IBCDC-RG2, clade 2.1) prepandemic candidate vaccines produced at 2 separate manufacturing sites.


METHODS
Two doses, each of which contained 3.75 microg of hemagglutinin antigen, were given 21 days apart either without adjuvant or with an adjuvant system containing 11.86 mg or 5.93 mg of tocopherol (AS03).


RESULTS
The AS03-adjuvanted A/Indonesia/05/2005 (NIBRG-14) vaccines were significantly more immunogenic than nonadjuvanted vaccine in homologous assays. Neutralizing cross-clade immunogenicity against clades 1, 2.2, and 2.3 was demonstrated at day 42 with all vaccines; at 6 months, seroconversion rates were highest for clade 2.2 (60.7%) and for clade 1 (38.3%). Adjuvantation was associated with increased short-term injection-site reactions (pain) in 80% of participants, with such reactions assessed as being of grade 3 severity for 4.0% of doses. No other safety or reactogenicity concerns were identified over 6 months of follow-up.


CONCLUSIONS
Humoral responses against the adjuvanted 3.75-microg hemagglutinin antigen vaccines from both manufacturing sites fulfilled European and US licensure criteria for immunogenicity for influenza vaccines.
Langley
Joanne M
JM
Canadian Center for Vaccinology, Dalhousie University and IWK Health Centre Halifax, Halifax, Nova Scotia, Canada. jmlangle@dal.ca
Frenette
Louise
L
Ferguson
Linda
L
Riff
Dennis
D
Sheldon
Eric
E
Risi
George
G
Johnson
Casey
C
Li
Ping
P
Kenney
Richard
R
Innis
Bruce
B
Fries
Louis
L
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000293:Adolescent; D000328:Adult; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D002170:Canada; D003429:Cross Reactions; D005260:Female; D006801:Humans; D007117:Immunization, Secondary / Q000379:methods; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D014481:United States; D014611:Vaccination / Q000379:methods; D055815:Young Adult
D000276:Adjuvants, Immunologic; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D007252:Influenza Vaccines