Posted by There is a great deal of activity on the bird flu vaccine front. Several different new techniques to make vaccines are being tested and so are additives to vaccines, called adjuvants, that boost the ability of the preparation to induce the body to make sufficient antibodies to protect us against infection. The smaller the dose needed for protection, the more people can be vaccinated for a given amount of production. Since we are talking about enough productive capacity to vaccinate a significant proportion of the world’s population in the event of a catastrophic pandemic, this is obviously a critical issue. When it comes to bird flu, the subtype of influenza A in birds designated H5N1, there is a special problem in determining whether the vaccine is effective or not and at what dose. Since a pandemic strain of H5N1, one that transmits easily from person to person, has yet to develop we can’t test to see if the vaccines really protect against infection in people. It is clearly unethical to infect people experimentally with existing strains. Current case fatality ratios are over 60%. So how do we know if the vaccines now being developed and tested will work or not?
If “work” means, protect against infection in a pandemic, we don’t. The best we can do is guess, based on the biology. Vaccines are designed to raise antibodies against the invading virus. There are different kinds of antibodies but the ones we are most interested in are the ones that neutralize the ability of the virus to infect human cells. They are called, naturally enough, neutralizing antibodies. We test for them in cell culture systems, seeing whether antibodies produced in healthy test subjects are sufficient to prevent infection in animal cells. Doing this requires a protocol and measurement procedure.
It turns out there is no standardized way of doing this. That means that comparing the effectiveness of the different vaccines depends on two uncertainties. One is the overall problem of the relationship between a measurement of neutralizing antibodies in a cell culture system and the desired ability of that level of antibody to protect against infection in human beings during a pandemic. This isn’t a pure guess. We have some information about this from seasonal influenza. The other is how the measurement of antibodies is made. There are different ways to make the measurement and often slight variations in the test procedure will produce very different answers.
Canadian Press’s Helen Branswell has an interesting piece on this problem:
A study comparing the tests being used by vaccine manufacturers to gauge the effectiveness of their H5N1 avian flu vaccines shows there is a lot of variation in the sensitivity of the tests, the British scientist leading the effort says.
Differences in the sensitivity of the tests mean companies could be underestimating or overestimating the power of their vaccines as they try to work out what is the smallest protective dose, experts admit.
As things stand now, there is no way to usefully compare the results of one company’s clinical trials for their vaccine with a competitor’s findings.
“If Company A’s assay (test) happens to be 10 times more sensitive than Company B’s, Company A and Company B could be evaluating the exact same thing but reach different answers about whether they worked or not,” says Dr. John Treanor, a vaccine expert who knows of the study but is not involved in the work. (Helen Branswell, Canadian Press)
Branswell was reporting on a study in progress by Dr. John Wood at the UK National Institute for Biological Standards and Control that is attempting to establish an international standard. Variation aside, effectiveness is measured in terms of the antibodies it produces in trial subjects, not a demonstrated ability to prevent infection during a pandemic. That’s the best we can do at the moment and probably it is good enough. We hope.
Meanwhile work on producing an effective vaccine or vaccines moves forward. The intensity of the work by many companies suggests that while the threat of bird flu has moved off the front pages of our newspapers, it is still considered a likely threat by commercial interests in the pharmaceutical industry.
Make of that what you wish. To me and most flu experts, it seems a pretty worthwhile wager.
June 23, 2008
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