The adjuvant puzzle piece

In an interview published today CDC Director Dr. Julie Gerberding had this to say:

Q: We hear a lot about Tamiflu and other anti-virals. Will Tamiflu protect people if there is a pandemic outbreak? And is there any point in stockpiling vaccine for the H5N1 strain when it seems like the virus is constantly mutating?

A: We are stockpiling Tamiflu. The challenge of the virus is that it could very easily acquire resistance to Tamiflu or any other drug and we can't rely on drugs per se as a magic bullet. We have to have a vaccine. We are stockpiling a very small amount of the prototype H5N1. It might offer some partial protection. But the process of the manufacturers learning how to make the H5 vaccine is something that really helps us jump-start the production process. (Jennifer Brooks, Gannett, via Morris County, NJ Daily Record)

But one of the things we learned from the prototype was it required an unusually large amount of viral protein (180 micrograms) divided into two equal doses, to elicit the level of antibody titer thought to be effective in protecting against infection. This is twelve times the amount needed in the current seasonal flu vaccines and far beyond the current production capacity needed to vaccinate any but a small fraction of the world's population. One estimate has it that if the world's entire production capacity were turned over to H5N1 (ignoring co-circulating subtypes, the seasonal flu strains) the prototype might suffice for a bit over 1% of the world's people (75 million out of 6 billion plus).

Hence much is riding on current trials that incorporate additives (adjuvants) to boost the vaccine's potency. The original trials didn't have any adjuvants, something some critics thought was a mistake, as now much time has been lost. Today Canadian Press's Helen Branswell (the world's best flu reporter) has a preview of the high stakes trials to see if adjuvanted vaccines work to increase potency.

In the coming weeks, at least two vaccine companies are expected to release clinical trial findings that could have an enormous impact on how many people worldwide will have access to flu shots if H5N1 avian flu triggers a pandemic.

[snip]

The trials are expected to provide the first real evidence of whether adding an inexpensive and readily available chemical called alum - aluminium salts - to an H5N1 vaccine will substantially lower the dosage required to protect people against the worrisome strain. (Branswell, Canadian Press)

Two companies, France's Sanofi Pasteur and Australia's CSL, will report results of alum-adjuvanted clinical trials soon. NIAID in the US will start trials in January with alum and a proprietary adjuvant from Chiron Corporation. As Branswell's story notes, use of the proprietary adjuvant has both regulatory and economic drawbacks (it is only licensed in Europe and would be more costly). Thus it seems to us it should only be used if it had significant advantages over alum, although what should be and what will be are not always the same in our cynical experience.

But before worrying about cost, it has to be shown that adjuvanting will work at all for this influenza subtype. There are reasons to think it might be extremely effective, reasons to think it might be moderately or only slightly effective, and reasons to think it won't work at all (Branswell reviews the evidence).

Some virologists worry that H5N1 is not very immunogenic and hence raising an immune response with any vaccine might be difficult. This is bad news on two counts: it means we might not be able to develop a vaccine at all, and the virus might be unusually virulent because of the lack of an immune response. Only further study (or worse, actual experience in a pandemic) will settle that question, but it is my guess this virus is not defective in immunogenicity, so an effective vaccine still seems like the best long range strategy.

Branswell's article, like all of her work, is highly informative, well researched and makes use of her unusually rich network of expert sources. This is another piece of the pandemic flu puzzle, but an extremely important one from the standpoint of public health.