Early Data Favorable for H5N1 Vaccine from Tissue-Culture Substrate

By Peggy Peck ,
VIENNA, 03 june 2008-- An H5N1 whole-virus vaccine grown in tissue culture seems both safe and effective in a two-dose regimen against avian influenza, found a clinical trial of nearly 300 volunteers.
The vaccine was effective in inducing neutralizing antibody at either 7.5 μg or 15 μg doses in a two-dose regimen and worked best without the use of alum adjuvant, Markus Muller, M.D., of Medical University of Vienna, and colleagues reported in the June 12 issue of the New England Journal of Medicine.
The highest neutralizing-antibody response (78.2%) was obtained after the 7.5-μg second dose without adjuvant. This was "equivalent to a rate of seroconversion of 69% and represented an increase by a factor of four or more in the neutralization titer after two doses of vaccine," they wrote.
Those data were "also similar to the levels of immunogenicity reported in a study of an egg-derived whole-virus H5N1 vaccine."
The data also "showed that the whole-virus clade 1-based vaccine can induce a substantial cross-neutralizing response against clade 2 and clade 3 strains," they wrote.
On the basis of the results, the 7.5-μg without adjuvant dose has been chosen for further development.
The randomized trial by the Baxter H5N1 Pandemic Influenza Vaccine Clinical Study Team recruited 275 adult volunteers (ages 18 to 45) who received two doses of vaccine 21 days apart.
The tested doses were 3.75 μg, 7.5 μg, 15 μg, and 30 μg of hemagglutin antigen with alum adjuvant or 7.5 μg or 15 μg without adjuvant.
Serologic analysis was performed at baseline and on days 21 and 42.
There were no serious vaccine-related adverse events. The most common injection-site reaction was pain, reported by 9% of patients who received the 7.5 μg without adjuvant dose versus 27% of patients who received 3.75 μg with adjuvant.
Headache was the most common systemic reaction and again it was more common among participants who received 3.75 μg with adjuvant -- 27% -- and least common among those who received 7.5 μg without adjuvant.
In a perspective that accompanied the study, Peter F. Wright, M.D., of Dartmouth Medical School, wrote that a tissue-culture-grown vaccine could overcome many of the timing issues created by vaccines produced in embryonated eggs, which are only available seasonally. The tissue-culture-grown vaccine, by contrast, could be produced at any time of year.
Moreover, the vaccine produced by Dr. Muller and colleagues "was not disrupted to form a subvirion vaccine," which was important because the findings suggest that the result was a vaccine with stronger immunogenicity.
The authors said the apparent absence of a dose-response relationship in the trial, although surprising, agreed with a number of studies of vaccine for pandemic influenza.
Although the reasons for a lack of a dose-response were unclear, they offered an explanation for when adjuvant was used -- in those cases the "ratio of adjuvant to antigen may be critical in determining the immune-enhancing effect rather than the antigen concentration alone."
Another possibility was that at low doses the response might be mediated by type 2 helper T cells, while at higher doses the response might be mediated by type 1 helper T cells.
The trial was supported by Baxter. Dr. Muller reported consulting and lecture fees from Baxter. Dr. Wright reported receiving grant support from Merck, GlaxoSmithKline, and Medimmune.
Primary source: New England Journal of MedicineSource reference:Ehrlich HJ, et al "A clinical trial of a whole-virus H5N1 vaccine derives from cell culture" N Engl J Med 2008; 158: 2573-84. Additional source: New England Journal of MedicineSource reference: Wright PF "Vaccine preparedness -- are we ready for the next influenza pandemic?" N Engl J Med 2008; 158: 2540-43.