Trial results for Glaxo's H5N1 vaccine released

Aug 27, 2007 (CIDRAP News) – The full results of a trial of GlaxoSmithKline's (GSK's) H5N1 influenza vaccine were released recently, showing that the vaccine in combination with an adjuvant produced an acceptable immune response at a low dose and may provide cross-protection against nonmatching H5N1 strains.

Writing in the Aug 18 issue of The Lancet, Isabel Leroux-Roels and colleagues reported that the lowest dose of adjuvanted vaccine, 3.8 micrograms (mcg), induced immune responses after two doses that met or exceeded all US and European criteria for vaccine licensing. Further, more than 75% of volunteers who received this low dose of adjuvanted vaccine, based on a clade 1 H5N1 virus, were shown to have neutralizing antibodies against a clade 2 strain. Equal doses of the vaccine with no adjuvant yielded significantly weaker responses.

The new report fleshes out preliminary results that GSK released in July 2006 and March 2007. The British company's 2006 report raised hopes that adjuvants could substantially boost the supply of prepandemic H5N1 vaccines by reducing the amount of antigen (active ingredient) needed in each dose. Several vaccine trials have shown that the hemagglutinin, or H, component of the H5N1 virus triggers a weak immune response in humans, so vaccines must contain relatively large amounts of it.

Seasonal flu shots typically contain 15 mcg of antigen for each of three flu strains, about four times as much as the lowest dose in the GSK vaccine trial. The first H5N1 vaccine licensed in the United States, made by Sanofi Pasteur, required two 90-mcg doses to induce a good immune response in about half of volunteers. With an adjuvant, the vaccine was shown to induce a good immune response in about two thirds of volunteers who received two 30-mcg doses.

The Lancet report describes, apparently for the first time, GSK's proprietary adjuvant. It is described as an oil-in-water–based emulsion, with the oil portion containing DL-alpha-tocopherol, or vitamin E, and squalene, an oil found in some fish oils, and the water portion containing a small amount of polysorbate 80, a nonionic detergent.

The vaccine used in the study was a split-virus formulation derived from a clade 1 H5N1 strain isolated from a Vietnamese patient in 2004. The trial was conducted in Ghent, Belgium, and involved 400 healthy men and women between the ages of 18 and 60. The volunteers were randomly assigned to receive one of eight vaccine formulations—3.8, 7.5, 15, or 30 mcg, with or without adjuvant. Each person received two doses, 21 days apart.

The researchers assessed humoral immunity by measuring hemagglutination-inhibition (HI) antibody titers and also testing for the presence of antibodies that could actually neutralize the H5N1 virus in the lab.

All eight vaccine formulations were well-tolerated, and no serious adverse events were reported. Pain at the injection site was the most common symptom in all groups but was more common in those who received the adjuvanted vaccine. General symptoms such as fatigue and headache also tended to be more common in the adjuvant group.

The adjuvanted preparations induced significantly stronger immune responses than the nonadjuvanted preparations at all doses, the report says. The 3.8-mcg dose with the adjuvant yielded HI antibody titers of 1:40 or higher in 84% (95% confidence interval [CI], 70.9% to 92.8%) of volunteers and fourfold increases in neutralization titers in 86% (95% CI, 72.8% to 94.1%). Without adjuvant, 3.8 mcg of vaccine induced similar results in only 16% and 37% of vaccinees. Even at the highest dose, 30 mcg, vaccine without adjuvant triggered similar HI titers and increases in neutralization titers in only 43% and 65% of vaccinees, respectively, the report says.

After the second dose, a significant dose-response effect was seen in those who received vaccine without the adjuvant but not in the adjuvant group.

After two doses, the adjuvanted vaccine at all dose levels met the European Committee for Medicinal Products for Human Use (CHMP) and the US Food and Drug Administration criteria for seroconversion and seroprotection, the report says. The unadjuvanted formulaton met the CHMP criteria only at the 30-mcg dose level.

To test the vaccine's ability to induce cross-protection against different H5N1 strains, the investigators assessed the generation of antibodies to an H5N1 virus derived from one isolated from an Indonesian patient in 2005 (a clade 2 virus). They found that after two doses, between 20% and 32% of vaccinees in the adjuvant groups generated protective HI titers, versus none of those in the nonadjuvanted groups. The neutralization assay showed a much stronger response, with 67% to 77% of those in the adjuvant groups showing a protective response, compared with less than 9% in the other groups. Mean titers of neutralizing antibodies were five to six times higher in the adjuvant groups than in the nonadjuvant groups.

The researchers write that the cross-clade neutralizing antibody responses imply that the vaccine could be used before the emergence of a pandemic caused by an H5N1 strain. "However, further analyses are warranted to confirm whether it could also confer high degrees of cross-protection against other pandemic drift strains," they add.

In an editorial in The Lancet, two flu experts who were not involved in the GSK vaccine trial hailed the findings as important progress.

The study "is the first to show significant antigen dose-sparing, high levels of immunogenicity in association with a novel adjuvant, and the induction of cross-clade immunity against A/H5N1 viruses," wrote Suryaprakash Sambhara of the Influenza Division at the US Centers for Disease Control and Prevention and Gregory A. Poland of the Mayo Vaccine Research Group at the Mayo Clinic in Rochester, Minn.

The findings suggest that the number of prepandemic vaccine doses could be stretched 20- to 25-fold, as compared with the 90-mcg dose required for the FDA-approved H5N1 vaccine, according to Sambhara and Poland. "This vaccine appears to be an important step forward in our ability to protect against the pandemic threat posed by highly pathogenic influenza A/H5N1 viruses," they add.

John Treanor, MD, a flu vaccine researcher and professor of medicine, microbiology, and immunology at the University of Rochester, said the key message of the results is that the adjuvant made a major difference in the immune responses.

"What has been demonstrated is that with the adjuvant you can use very low doses of hemagglutinin, which are as good as or better than what you see with higher doses of antigen without adjuvant," Treanor told CIDRAP News. The enhanced antibody response creates the possibility of cross-protection against nonmatching strains, he added.

He also said the report is helpful in that it describes the formulation of the GSK adjuvant, "so people know what they're talking about."

This study and several others "have, I think, demonstrated very convincingly that oil-and-water emulsions which contain squalene are a very good adjuvant for pandemic flu vaccines," he added.

Treanor said oil-and-water adjuvants were used as long ago as the 1950s. "I think the advance is that the formulation with squalene gives them a better toxicity profile," he commented, adding that the lack of serious side effects is an important finding.

But he stopped short of calling the GSK vaccine the most promising H5N1 vaccine tested so far. That's hard to judge, he said, "because none of these studies really compare vaccines of different types with each other," he said.

Also, he said, "There's a general problem in the field in that the assays are not very well standardized between labs, which complicates making comparisons between studies."

As for the idea that vaccines like GSK's could be used before a pandemic emerges, Treanor commented, "I think the balance of professional opinion is that we should hold off on vaccinating till there's a pandemic emerging. Not everyone agrees, but most think the best bet is to keep them in a stockpile." One reason for that, he said, is the swine flu episode of 1976, in which millions of Americans were vaccinated to prepare for a flu pandemic that never materialized.

Leroux-Roels I, Borkowski A, Vanwolleghem T, et al. Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomized controlled trial. Lancet 2007 Aug 18;370:580-9 [Abstract]

See also:

Mar 6 CIDRAP News story "Glaxo H5N1 vaccine may work against multiple strains"

Jul 26, 2006, CIDRAP News story "Glaxo says its H5N1 vaccine works at low dose"

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