Dose-Sparing Avian Flu Vaccine Shows Promise in Early Trials

BEIJING, Sept. 7 -- A potentially dose-sparing avian influenza vaccine containing inactivated whole particles of the virulent H5N1 strain evoked good immune responses at low doses in early clinical trials, a Chinese-British team found.

The vaccine was safe, and was most effective at eliciting virus-specific antibodies if given in two doses with aluminum hydroxide adjuvant four weeks apart, reported Jiangtao Lin, M.D., of the Chinese-Japanese Friendship Hospital here, and colleagues, in the online version of The Lancet.

"These findings identify a potential dose-sparing approach that could be crucial for a global supply of pandemic vaccine," wrote Iain Stephenson, M.D., of the Leicester Royal Infirmary, in England, in an accompanying editorial.

Foreseeing a shortage of vaccine should the pandemic H5N1 strain of avian flu leap from birds to humans, the World Health Organization has advocated investigations into dose-sparing strategies, such as the use of whole-virion vaccine and adjuvants.

Seasonal influenza shots are split vaccines that elicit a response by presenting to the immune system the viral surface proteins hemagglutinin and neuraminidase. Additionally, seasonal flu shots are usually not given with adjuvant, according to the WHO.

But avian flu is a bird of a different feather, and the best approach may be one that combines the powerful immunogenicity of a whole inactivated virus with adjuvant boosting, according to Dr. Lin and colleagues.

"Our trial suggests that an H5N1 vaccine manufactured and formulated with both of these approaches is well tolerated and immunogenic," they wrote.

Worldwide, vaccine manufacturers can produce about 300 million doses of trivalent seasonal influenza vaccines every six months, Dr. Stephenson wrote. Theoretically, they could produce 900 million doses of a monovalent H5N1 vaccine, but that would cover just 450 million people, because of the two doses needed for an immunogenic response.

In addition, "clinical studies of split H5N1 vaccines are disappointing," he continued. "A U.S. study of non-adjuvanted H5N1 vaccine found that only two doses containing 90 ?g hemagglutinin per dose induced acceptable antibody levels. In France, two 30 ?g doses of alum-adjuvanted H5N1 vaccine were immunogenic, with no effect of alum adjuvant at lower doses. So, within current manufacturing constraints of split vaccines, supplies of either of these two vaccines would be limited to 75 or 225 million people only."

The whole virion approach also preserves the estimated 20% to 30% of antigens typically lost during the split-vaccine manufacturing process, thereby making more vaccine available.

In their phase I double-blinded study, Dr. Lin and colleagues randomly assigned 120 healthy volunteers, ages 18 to 60, to received either placebo or the inactivated whole-virion influenza A (H5N1) vaccine at one of four doses: 1.25 ?g, 2.5 ?g. 5 ?g, or 10 ?g hemagglutinin per dose with aluminium hydroxide adjuvant on days 0 and 28.

The investigators obtained serum samples from the volunteers on days 0, 14, 28, 42, and 56. The samples were evaluated for hemagglutination inhibition and assayed for virus neutralization.

They found that all four formulations of the vaccine were well tolerated, with no serious adverse events. Most local events such as injection site reactions and pain, and most systemic reactions such as myalgia, headache, fatigue or nausea, were mild and transient, the investigators wrote.

All formulations produced an antibody response after the first dose. The most vigorous antibody response, 78% seropositivity for neutralizing antibodies, was seen after the second 10 ?g dose was delivered. In addition, 96% of volunteers in this group had hemagglutinin inhibition responses.

The two-dose regimen met all European regulatory requirements for annual licensing of seasonal influenza vaccine, the authors noted.

"Lower doses of this vaccine could achieve immune responses equivalent to those elicited by adjuvanted or non-adjuvanted split-virion vaccines. The use of a whole virion vaccine could be more adaptable to the antigen-sparing strategy recommended by WHO for protection against an influenza pandemic," they wrote.

The investigators noted that because whole-virion vaccines have been known to induce more adverse events in children, investigators should be cautious in their approach to testing such vaccines in children and in the elderly.