Antigen-Sparing Strategy Could Up Availability of Bird Flu Vaccine

GHENT, Belgium, Aug. 16 -- Production of avian influenza vaccine could substantially increase with use of an antigen-sparing strategy that increases levels of neutralizing antibodies, investigators here reported.

Antibody production increased by as much as six-fold in healthy volunteers given a vaccine formulated with an oil-in-water emulsion adjuvant, Geert Leroux-Roels, M.D., of Ghent University, and colleagues reported online and in the Aug. 18 issue of The Lancet.

At the lowest antigen dose of 3.8 g, the immune response against a recombinant avian flu strain met or exceeded FDA and European Union criteria.

"The cross-clade neutralizing antibody responses recorded imply that such a vaccine could be deployed before pandemic outbreak, which is an important mitigation strategy proposed for pandemic influenza," the authors concluded.

The antigen-sparing approach should be maintained as an important back-up strategy to ramp up vaccine production once a specific pandemic strain has been identified, they added.

The spread of H5N1 avian influenza has sparked global concern about the potential for a pandemic. The virus has an H5 subtype of hemagglutinin antigen against which most people do not have immunity, the authors noted. Of the 318 cases of bird flu reported thus far to the World Health Organization, 192 (60%) proved to be fatal.

According to WHO, the global population has entered phase three of a six-step pandemic alert, prompted by the virus' evolution into a strain capable of efficient human-to-human transmission.

Conventional seasonal influenza vaccines are not expected to protect against H5N1. Moreover, the reverse-genetics process used to produce most vaccines has an antigen yield that is less than half that achieved with interpandemic strains, said Dr. Leroux-Roels and colleagues.

Also of concern, the population's lack of immune protection against H5 hemagglutinin means that single-dose vaccination used for seasonal influenza is unlikely to be sufficient.

Against the background of a pandemic in evolution, the use of the adjuvant to improve vaccine immunogenicity has emerged as a crucial antigen-sparing strategy, the authors stated.

In the current study investigators evaluated the safety and immunogenicity of a recombinant H5N1 split-virion vaccine formulated with a proprietary 10% oil-in-water emulsion adjuvant system.

The oil phase contained 5% DL-?-tocopherol and squalene, and the aqueous phase contained 2% of the non-ionic detergent polysorbate 80.

A total of 400 healthy adult volunteers were randomized to four groups that received vaccines containing 3.8 g, 7.5 g, 15 g, or 30 g of H5 hemagglutinin antigen. Half the participants received vaccines with the adjuvant and half received nonadjuvanted vaccines. Each participant received two vaccine doses administered 21 days apart.

All eight vaccine formulations were well tolerated, and no immediate allergic reactions or serious adverse events were reported, according to the authors.

Injection-site pain was the most common local symptom in all eight groups but occurred significantly more often in patients who received adjuvanted vaccine (P=0.002 to P<0.0001).

The most frequent general symptoms were fatigue and headache, which also occurred more often in patients who received adjuvanted vaccine.

A hemagglutinin dose-response effect was seen in all groups after the first vaccine dose, but only patients assigned to nonadjuvanted vaccines had a dose-response effect after the second dose.

The three highest doses of the adjuvanted vaccine met the EU Committee on Medicinal Products for Human Use criteria for seroconversion after the first dose, whereas none of the nonadjuvanted vaccines did.

After the second dose, all of the adjuvanted formulations met European Union and FDA criteria for seroconversion and seroprotection, whereas only the 30-g nonadjuvanted vaccine did.

To assess the vaccine's ability to induce cross-reactivity against drifted H5N1 strains, the investigators examined humoral immunity against a strain derived by reverse genetics from a drifted H5N1 isolate.

After the first dose of adjuvanted vaccine, seroconversion rates increased by 27% to 54%, increasing to 67% to 77% after the second dose. In contrast, the nonadjuvanted formulation had a neutralizing seroconversion rate of less than 9%.

Along with the difference in seroconversion, geometric mean titers associated with neutralizing response were five to six times greater with the adjuvanted vaccines than with the nonadjuvanted formulations.

"The ability of the 3.8-g dose of adjuvanted split-virion vaccine to induce cross-immunity . . . in more than three-quarters (seroconvesion rate) of individuals with a [geometric mean titer] that is six times higher than the nonadjuvanted formulation, represents a significant antigen sparing that could increase the number of recipients of the pandemic influenza vaccine," the authors concluded.

In a commentary about the study, Suryaprakash Sambhara, M.D., and Gregory A. Poland, M.D., of the CDC, suggested the results could provide impetus for prepandemic immunization of at least some individuals.

"Their study lends support for considering a strategy of immunizing some groups with prepandemic vaccines for preparedness in the event of a pandemic from an H5N1 virus," they wrote.

"This vaccine appears to be an important step forward in our ability to protect against the pandemic threat posed by the highly pathogenic influenza A/H5N1 viruses," said Drs. Sambhara and Poland.