THE PANDEMIC VACCINE PUZZLE Part 4: The promise and problems of adjuvants

Editor's note: This is the fourth in a seven-part series investigating the prospects for development of vaccines to head off the threat of an influenza pandemic posed by the H5N1 avian influenza virus. The series puts promising advances in vaccine technology in perspective by illuminating the formidable barriers to producing large amounts of an effective and widely usable vaccine in a short time frame. Part 3 discussed the immunologic challenges posed by the H5N1 virus, including its poor immunogenicity when incorporated in vaccines and the difficulty of assessing immune responses to the vaccines.

Oct 30, 2007 (CIDRAP News) – Adjuvanted vaccines appear to hold the greatest promise for solving the grave supply-demand imbalance in pandemic influenza vaccine development. They come with obstacles—immunologic, regulatory, and commercial—but they also have generated more excitement than any other type of vaccine thus far.

In an example of the hope being hung on adjuvants, the WHO last week issued a statement declaring that the pandemic vaccine supply is "sharply" increasing and forecasting that annual manufacturing capacity will rise to 4.5 billion two-dose courses by 2010 (see Bibliography: WHO 2007: Projected supply). The forecast is based on the expectation that flu vaccines made in 2010 will include an adjuvant permitting the use of just one-eighth of current vaccines' antigen content. (Adjuvants are chemicals that are incorporated in some vaccines to improve response to the vaccines' active ingredient. Adjuvants make it possible to reduce the dose of antigen in a vaccine without dampening the immune response.)

"We have H5N1 to thank for opening up the flu research field, which was absolutely creeping along," said Dr. Arnold Monto, a flu epidemiologist at the University of Michigan, who has long research experience with live-attenuated vaccine. "We've always known that flu vaccine was good, but not great—not a 21st century vaccine with 95% protection—but there was a feeling that it was good enough. But H5N1 changed the risk-benefit ratio so that we are willing for instance to work with adjuvants, which may have theoretical risks but certainly may well afford tangible benefits. We're going to learn a whole lot about the immunology of protection that we haven't learned in the past" (see Bibliography: Monto 2007).

While adjuvants hold the greatest promise for dose-sparing, they also provoke trepidation because they are by definition immune-system activators. While many have been tested over the years, few have entered the market, because they proved too reactogenic to be acceptable to consumers or safe. Only one set of adjuvants, aluminum salts or alum (aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate), is licensed in the United States. Aluminum adjuvants and MF59, an oil-in-water emulsion that contains squalene (an oil found in some fish oils), are licensed in Europe (see Bibliography: Petrovsky 2007).

No adjuvanted flu vaccine is licensed in the United States—a notable oversight since federal health authorities urged such a vaccine be investigated as a preparedness measure after the pandemic of 1957 (see Bibliography: Strikas 2005). Fifty years later, the need to seek regulatory approval for novel components in adjuvanted pandemic vaccines could prove a barrier to rapid market entry of formulas that look promising.

Adjuvants old and new
Early hopes for an adjuvanted H5N1 vaccine focused on alum, because it is well-understood and widely licensed, but those formulas have proved disappointing. A phase 1 study of alum-adjuvanted vaccine made by the Chinese company Sinovac Biotech achieved acceptable levels of protection using two doses of only 10 micrograms (mcg) of flu antigen—but that formula was based on an inactivated whole virus, a flu-vaccine type that is licensed in the European Union but not currently used in the United States (see Bibliography: Lin 2006).

Two other alum-adjuvanted vaccines that used whole viruses have shown some promise for antigen sparing. At a February 2007 World Health Organization (WHO) meeting, Norbert Hehme of GlaxoSmithKline Biologicals reported that a regimen of two 15-mcg doses met EU criteria for immune response (see Bibliography: Hehme 2007). And in May, Hungarian investigators reported that they had achieved an acceptable immune response in a small study using a formula (based on a seasonal vaccine already licensed in the EU) containing a single dose of only 6 mcg (see Bibliography: Vajo 2007). Two alum-adjuvanted vaccines that used the split-virus formulation common in the United States have reported levels of immune response acceptable to regulators at two doses of 45 mcg (see Bibliography: Keitel 2007) or 30 mcg (see Bibliography: Bresson 2006). But those levels of antigen are so high that deployment of those vaccines would not allow significant dose-sparing.

The most provocative news in dose-sparing has come in the past several months. In August, scientists working with a GlaxoSmithKline formula published a trial of a two-dose regimen of an inactivated split-virus vaccine adjuvanted with a proprietary oil-in-water emulsion; after the second injection, even the lowest dose of 3.8 mcg exceeded EU criteria for immune response (see Bibliography: Leroux-Roels 2007). And in September, Sanofi Pasteur reported in a press release that an inactivated vaccine adjuvanted with the company's own proprietary formula induced EU-accepted levels of protection after two doses of 1.9 mcg.

Regulatory barriers loom
Like many other aspects of pandemic planning, adjuvants' ability to solve some of the challenges of preparedness will depend on how rapidly a pandemic arrives. That is because the most promising vaccines rely on formulas that have not yet been licensed in the United States. The Food and Drug Administration (FDA) has indicated that pandemic vaccines made in the same manner as an already-licensed seasonal vaccine may be treated only as a "strain change," in an accelerated approval process by which components are swapped out of existing seasonal flu vaccines each spring. But since there are no adjuvanted seasonal flu vaccines currently licensed in the United States, antigen-sparing pandemic vaccines may require a full Biologics License Application—the complete portfolio of testing and data, on both the product and the manufacturing facility, that is demanded of any new drug submitted for licensure and can take years to assemble (see Bibliography: FDA 2007: Guidance for industry: clinical data needed to support the licensure of pandemic influenza vaccines).

Moreover, at the moment both the FDA and the European Union's drug agency consider adjuvants to be a component of vaccines, not a product separate from vaccines—implying that adjuvants can be brought forward only as part of a precise antigen dose/adjuvant combination that must be tested for safety and efficacy, probably in a "non-inferiority" trial against the same antigen dose without adjuvant, and then submitted for licensure (see Bibliography: European Agency for the Evaluation of Medicinal Products 2005; FDA 2007: Guidance for industry: clinical data needed to support the licensure of seasonal inactivated influenza vaccines).

"We have not taken the position that an adjuvant can be thought of as a stand-alone product," Dr. Pamela MacInnes of the National Institutes of Health said at an FDA advisory committee meeting last February. "It's a product that has antigen in combination with an adjuvant that comes forward for licensure" (see Bibliography: FDA 2007: Committee meeting transcript).

Mixing and matching
There is currently no regulatory pathway by which adjuvants may be submitted for approval as products by themselves—or may be paired with a separately manufactured antigen, perhaps one produced by another company. Regulators acknowledge that could stand in the way of, for instance, converting the already-manufactured vaccine in the national stockpile (which was purchased under the 90-mcg-dose license granted Sanofi Pasteur earlier this year but is held in bulk) to an adjuvanted vaccine that could be stretched much further.

"There probably are more concerns about an antigen made with one manufacturing process and an antigen made with another manufacturing process and whether when those are mixed with ideal adjuvant X in two potentially different circumstances or time points, that could raise a bunch of issues about formulation, stability, immunogenicity, safety," Dr. Jesse Goodman, director of the FDA's Center for Biologics Evaluation and Research, said at the FDA meeting (see Bibliography: FDA 2007: Committee meeting transcript).

The US Department of Health and Human Services (HHS) issued $132.5 million in contracts in January 2007 to three companies—GlaxoSmithKline, Iomai, and Novartis—to study antigen technology, including the possibility of mixing and matching adjuvants with separately manufactured antigens (see Bibliography: GSK 2007; Iomai 2007; Novartis 2007: Novartis receives US government contract). Manufacturers have welcomed the government interest because negotiating combinations of components from different companies is fraught with antitrust and intellectual-property pitfalls.

"I have heard a lot of people say they expect problems with adjuvanted vaccines," said Hedwig Kresse, an associate analyst for infectious diseases with the British-based market analysts Datamonitor. "It is a technology that definitely has some potential, but there are a lot of issues that need to be addressed first" (see Bibliography: Kresse 2007).

The pandemic vaccine puzzle

Part 1: Flu research: a legacy of neglect
Part 2: Vaccine production capacity falls far short
Part 3: H5N1 poses major immunologic challenges
Part 4: The promise and problems of adjuvants
Part 5: What role for prepandemic vaccination?
Part 6: Looking to novel vaccine technologies
Part 7: Time for a vaccine 'Manhattan Project'?
Bibliography

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