Chinese report results for whole-virus H5N1 vaccine

Sept 7, 2006 (CIDRAP News) – In a human trial in China, a whole-virus H5N1 avian influenza vaccine generated an immune response with a relatively low dose of antigen, suggesting that it could be used to immunize more people than may be possible with some other vaccines under development.

The study, published online today in The Lancet, showed an adequate immune response in 78% of volunteers after two 10-microgram (mcg) doses of the vaccine plus an aluminum hydroxide (alum) adjuvant. That exceeds the European Union's requirement of an acceptable response (a hemagglutinin-inhibition titer of 40 or more) in 70% of volunteers.

The vaccine is made by Sinovac Biotech in Beijing, China, from an inactivated strain of H5N1 known as Vietnam/1194/2004. The report says that Sinovac was involved in designing and monitoring the study but played no role in collecting the data or writing the report.

The randomized, placebo-controlled, double-blind study involved 120 adults (aged 18 to 60). They were divided into five groups of 24, with each group receiving either a placebo or 1.25, 2.5, 5, or 10 mcg of the vaccine.

Each volunteer received the vaccine on the first day of the study and 28 days later. Serum samples were assessed for evidence of an immune response on days 0, 14, 28, 42, and 56.

An antibody response was seen after the first injection at all dose levels. The highest response (78% seropositivity) was seen in the 10-mcg group after two doses.

The investigators reported that all four doses were well tolerated, even though whole-virion vaccines are generally thought to cause more reactions than split-virion vaccines. No serious reactions were reported, and most local and systemic reactions were mild and brief. Three people dropped out of the study, and one person was excluded from the final analysis.

The authors concluded that the dose required to reach an acceptable immune response was much lower than for vaccines reported in previous studies. Two reports published earlier this year described trials of a split-virus H5N1 vaccine developed by Sanofi Pasteur. The reports said two 90-mcg doses of nonadjuvanted vaccine or two 30-mcg doses of adjuvanted vaccine were required to produce the desired immune response.

(In July, GlaxoSmithKline reported a good immune response in 80% of volunteers who received a dose of only 3.8 mcg of the company's adjuvanted H5N1 vaccine. However, a full report of those findings has not yet been published.)

"The manufacturing capacity for an H5N1 vaccine would increase if a whole-virion vaccine is used, because 20% to 30% of vaccine antigen is expected to be lost during the disruption process in the preparation of split-virion vaccines, according to our experience with seasonal influenza vaccine," the Chinese researchers write.

In an accompanying commentary, Iain Stephenson, MD, of the Infectious Diseases Unit at Leicester Royal Infirmary in Leicester, England, writes that the findings point up of "a potential dose-sparing approach that could be crucial for a global supply of pandemic vaccine."

He says that trial results for split-virion H5N1 vaccines have been disappointing, because within current manufacturing constraints, the two such vaccines under development would yield only enough to vaccinate 75 million to 225 million people.

Though whole-virion vaccines generally produce a better immune response than split or subunit vaccines, development of whole-virion H5N1 vaccines has been delayed, Stephenson writes. He says it is difficult for manufacturers that produce split seasonal vaccines to switch production approaches and processing methods.

Stephenson cautions that whole-virion vaccines have been associated with febrile reactions in children and emphasizes that careful investigation is needed before such vaccines can be widely used.

It remains to be seen whether whole-virion vaccines can induce the broad cross-reactive response that would be needed to treat a variety of H5N1 viruses, Stephenson writes.

Lin J, Zhang J, Dong X, et al. Safety and immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine: a phase 1 randomised controlled trial. Lancet 2006 (early online publication, Sep 7) [Abstract (registration required)]

Stephenson I. H5N1 vaccines: how prepared are we for a pandemic? (Commentary). Lancet 2006 (early online publication, Sep 7)

See also:

May 12 CIDRAP News story "Sanofi reports results for H5N1 vaccine with adjuvant"

Jul 26 CIDRAP News story "Glaxo says its H5N1 vaccine works at low dose"

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