Safety and immunogenicity of multiple and higher doses of an inactivated influenza A/H5N1 vaccine.
BACKGROUND
H5N1 avian influenza represents an episodic zoonotic disease with the potential to cause a pandemic, and antiviral resistance is of considerable concern. We sought to generate high-titer H5N1 antibodies in healthy volunteers for the purpose of developing hyperimmune intravenous immunoglobulin.


METHODS
We conducted a dose-escalating, unblinded clinical trial involving 75 subjects aged 18-59 years. Three cohorts of twenty-five subjects were enrolled sequentially and received 90, 120, or 180 microg of H5N1 A/Vietnam/1203/04 vaccine in 4 doses administered approximately 28 days apart.


RESULTS
No statistically significant dose-related increases in the geometric mean titers (GMTs) of serum hemagglutination inhibition antibody were observed when the 90-microg, 120-microg, and 180-microg cohorts were compared. When the cohorts were analyzed together to determine the effect of additional vaccinations, the GMTs of hemagglutination inhibition antibody after the first, second, third, and fourth vaccinations were 1:15.7, 1:22.2, 1:36.0, and 1:32.0, respectively (first vaccination vs. baseline, P<.001; second vs. first vaccination, P=.02; and third vs. second vaccination, P<.001). The microneutralization GMTs after the first, second, third, and fourth vaccinations were 1:17.5, 1:33.1, 1:55.7, and 1:68.4, respectively (P<.001 for all comparisons).


CONCLUSIONS
The results of our study suggest that a third and fourth dose of the H5N1 A/Vietnam/1203/04 vaccine may result in higher hemagglutination inhibition and microneutralization GMTs, compared with the GMTs resulting from fewer doses. There was no benefit to increasing the dose of the vaccine.


BACKGROUND
Clinical Trials.gov identifier: NCT00383071.
Beigel
John H
JH
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. jbeigel@niaid.nih.gov
Voell
Jocelyn
J
Huang
Chiung-yu
CY
Burbelo
Peter D
PD
Lane
H Clifford
HC
D000293:Adolescent; D000328:Adult; D000914:Antibodies, Viral / Q000097:blood; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006386:Hemagglutination Tests; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000009:adverse effects* / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009500:Neutralization Tests; D013997:Time Factors; D055815:Young Adult
D000914:Antibodies, Viral; D007252:Influenza Vaccines