Medical Examiner

To Boost or Not To Boost

The United States’ swine flu vaccines will leave millions worldwide unprotected.

A vaccine for the H1N1 virus

In the race between vaccine makers and the swine flu virus they hope to knock off track, the results of the first heat—the vaccine trials published last week —brought great news: The vaccines now entering the production pipeline appear to be fast, effective, and (so far as a standard trial can tell) safe. The best of this news is that the vaccines appear to work well even at single standard seasonal-flu doses of 15 micrograms—rather than requiring a 30-microgram dose or, worse yet, two 30-microgram doses spaced over two to four weeks, as officials had feared would be necessary to produce a strong antibody response to this new virus.

These results effectively double or quadruple the vaccine supply now being manufactured by factories in Europe, Canada, and elsewhere. * (The United States makes very few vaccines; our facilities are too busy making more-profitable drugs that treat pain, various mental disorders, and erectile dysfunction.) Set aside for a moment the legitimate question of whether the swine flu might outrun even this accelerated vaccine train. If the fast-tracking efforts continue to work and the flu peaks closer to Christmas than Columbus Day, this robust and effective vaccine supply stands to sharply check swine flu in the United States, saving anywhere from a few thousand to 50,000 lives.

But what if we could save two to four times that many lives by vaccinating another 200 million to 300 million people worldwide?

Well, we could have—but the United States effectively decided not to do so when it ordered its vaccine supply. Back in May, many other countries ordered swine flu vaccines that include boosters, called adjuvants, that reduce by half or more the amount of antigen (the imposter or inactivated infectious agent) a vaccine requires to be effective. The United States, however, ordered almost all of its doses in the nonadjuvant, or unboosted, form—an older model of vaccine, considered the U.S. standard, that uses more antigen but creates vaccines that are (at least theoretically) safer. That safety, however, comes at the cost of exhausting the precious antigen supplies much faster — and leaving hundreds of millions elsewhere unvaccinated.

I don’t want to be flip about this. Adjuvants stir unease among many virologists and public-health experts. Adjuvanted vaccines take a different path to creating the antigen and contain elements, such as aluminum salts or mineral oil, that nonadjuvant vaccines do not. This makes them more complex; as with many drugs, virologists tell me, no one really knows precisely how adjuvants actually work. Some adjuvants, though generally not used in humans, can cause nasty problems such as joint degeneration, tissue damage, or inflammation. And when an adjuvanted vaccine was given to some 48 million individuals during the 1976-77 swine flu false alarm, about 500—more than was usual among that many people—developed a paralyzing autoimmune affliction known as Guillain-Barré syndrome, and 25 of them died. That adjuvant mix is no longer in use.

Yet as the excellent Effect Measure blog explains, the more-conventional vaccines without adjuvants also pose a risk—very small, but we’re parsing small risks here—to cause such adverse effects. (Such risks are too small to show up in vaccine trials. When vaccines do create serious adverse effects—a rare event—they tend not to show until the shot’s been given to perhaps 500,000 or even 1 million or more people; they don’t pop up on trials like those reported last week, which used just a few hundred volunteers.) So while the unboosted versions enjoy a historical edge in vaccine safety, that advantage is small, and it varies widely depending on the adjuvants used.

Finally, even though the “safer,” unboosted swine flu vaccine did well in the trials posted last week, there’s still a chance—tiny, but probably bigger than in the boosted version that was tested—that it won’t prove very effective in actual use. The unboosted version created a strong antibody response. But the trials assume that this level of antibody response will resist the swine flu as effectively as the same level resists the seasonal flu. That assumption is almost certainly valid but can be proved only after tens of millions of vaccinated people have been exposed to the virus. So this unboosted vaccine runs a very small extra risk—equal, for all practical purposes, to the boosted vaccine’s added risk of adverse events—that it simply won’t work well. If it doesn’t, we’ll end up wishing we used the beefier, boosted version instead.

Given all that, how do you decide which vaccine to order?

It depends on how you phrase the question. The Centers for Disease Control and Prevention asks—and most Americans also want to know—”Which vaccine is safer?” Here, the unboosted version, thrusting its slightly smaller hypothetical risk way out before it, wins by a nose.

But health officials and advocates in Canada, Europe, and Asia, at the United Nations, and at the Gates Foundation instead ask, “Which vaccine will let us vaccinate the most people?” Here the boosted version, because it uses about half as much antigen per dose, wins by a couple of laps. (The efficiency gain varies by adjuvant and vaccine. With some vaccines, adjuvants let you make three or more times as much vaccine. With this swine flu vaccine, it lets you make twice as much.) That’s why Canada, Europe, and many other countries have ordered mostly adjuvanted versions.

The painful part is that the adjuvant being used to boost these swine flu vaccines, known as MF59, has been used to boost seasonal flu vaccines in Europe for 12 years now—and those vaccines have caused no more adverse effects than our unboosted U.S. vaccines have. * It appears to be quite safe. Vincent Racaniello, a prominent virologist at Columbia University who also keeps the Virology Blog, told me his European colleagues are aghast that the United States doesn’t use the adjuvanted seasonal flu vaccines. “They think we’re nuts,” Racaniello told me. “They simply don’t understand it.”

But, as Racaniello noted, what his European colleagues really don’t understand—and what the CDC and other U.S. health officials understand all too well—is that this country’s anti-vaccine sentiment is so strong, and its distrust of scientists so great, that the sensible, even obvious public-health decision about adjuvanted flu vaccines is an untenable political decision.

“There’s simply no way,” as Racaniello put it, “that you want to buck that sentiment.”

And so we have ordered, with only rare discussion of the consequences, some 195 million doses of an unboosted vaccine that consume enough antigen to make 390 million doses of boosted vaccine. * Even worse, of those 195 million doses, we’ll probably use, given our vaccination anxiety, perhaps 60 million to 100 million.   If that is the case, we’ll probably throw away about 100 million or more doses.

Our vaccine anxiety runs high—and it, along with a growing distrust of science and medicine and our relentless focus on individual rather than community health, has led us to short the rest of the world some 200 million to 250 million doses. Even if the virus retains its present, relatively “mild” course—killing about as many as the seasonal flu but more heavily concentrated on adults under 60, especially the sick and the pregnant—this could mean some 20,000 to 50,000 deaths.

It is natural to look after your own. It’s understandable to seek maximum safety. But from masthead height, this looks mighty ugly. Our insistence on the safest vaccine possible means halving the supply, even as our own domestic drug factories are devoted to more-profitable drugs. Effectively, we’re taking two doses from others to give us one. We come off looking rather like the proverbial first-class passengers who, having scoffed at the need for lifeboats because they take up deck, now scramble into the few rafts while steerage looks on.

We could, of course, make some amends by giving away half of the 195 million doses we have lined up, since they’re going to go twice as far as anticipated. But with health care and vaccines so laden politically, that, too, seems unlikely.

Correction, Sept. 21, 2009: This piece originally suggested that we will have double or quintuple the expected supply of swine flu vaccine. We will have double or quadruple the vaccine. (Return  to the corrected sentence.) Also, the available supply of antigen could create 390 million doses of boosted vaccine, not 380 million. (Return  to the corrected sentence.)

Correction, Sept. 21, 2009: This piece originally and incorrectly stated that MF59 adjuvant has been used in both Canada and Europe for the last 12 years. Europe has used the adjuvant for that long; Canada has not. (Return  to the corrected sentence.)