In a disturbing post at ScienceInsider, Jon Cohen and Martin Enserink explain why the swine flu vaccine is running so late. Or at least they try to explain why it's so late. For while all the suppliers are running into problems, we're not allowed to know what they are.
The delays are substantial and critical. They leave us naked as the flu spreads through the country. The flu has now killed 1000 people, over 100 of them children. Even as this happens, the delivery dates keep moving back and the delivery amounts keep shrinking. As recently as a month ago, the CDC was telling us that we'd have 40 million doses by the end of this month. Last week, they were saying 30 million doses. Now they're saying 16 million doses and not making any promises beyond that.
The U.S. contracted with five companies to supply vaccine. Only one, MedImmune -- the company supplying the adjuvanted FluMist product -- has come close to its promised delivery schedule. But because we're so leery of adjuvanted product, we ordered only 12.8 million doses from MedImmune. The other four companies, meanwhile, are all running badly behind. Why? When ScienceInsider pressed Nicole Lurie, the assistant secretary for preparedness and response at HHS, for answers, she essentially she couldn't say.
For proprietary reasons, Lurie would not name the delay issues at each manufacturer, but said "one company was just really overoptimistic" in its delivery predictions to HHS. Initially, all of the makers of inactivated vaccine had trouble with the "potency assay" used to ensure that 15 micrograms of influenza antigens are present in each dose. Once that was corrected, said Lurie, this company lost 20% to 35% of its antigen during the "recalibration." Unfortunately, said Lurie, the company did not notify HHS of the problem. "They thought they were going to compensate by getting their yield up but they never let us know," she said. "When we learned of problem, it was over and there was nothing we could do, which is too bad because we could have helped."
After Columbus Day on 12 October, HHS learned about delays at two of the other companies. One had a new production line to fill doses of vaccine into individual syringes. "Getting up the new production lines with prefilled syringes was really slow," Lurie said. The third company had "major production problems" that Lurie said she could not describe in detail for proprietary reasons. Basically they had difficulty making "acceptable" vaccine that did not contain an immune booster called an adjuvant, which is used in several countries but not the United States.
The final company wanted to supply its own country with vaccine before shipping product to the United States, which Lurie said would begin next week. She did not identify the company, but Australia's CSL earlier said it would supply its country before exporting the product.
Given the drug industry's recent problems with what one might generously call overpromising (and with what Lurie here even more generously calls "overoptimism"), this is troubling. We contracted with four companies, and each of the four was apparently either overoptimistic or misleading in its delivery predictions. The CDC apparently found them convincing -- and was apparently left blind to the delays until the companies revealed them at a very late hour. The CDC now tells us simultaneously that no one could have foreseen the problems, for they came (at four different companies) from a perfect storm, or four perfect storms -- and that these perfect storms are all to be expected, because this is vaccines, and vaccines are slow and glitchy.
If they have so much experience making the product [asked ScienceInsider], why so many snafus with the pandemic vaccine? "Almost every flu season, something goes wrong," said Lurie, emphasizing that she was referring to manufacturing, not safety.
I don't think the CDC is conniving here. But it appears it has let itself be misled by an industry that has a remarkably well-known record of misleading. It remains unexplained how this industry enjoys so strong a presumption of goodwill and integrity that even in a supply issue so directly vital to public health, we're not allowed to know more about what slowing things down. I like industrial secrets as much as the next person. Doubtless these companies must keep certain hard-won information under wraps. But it would seem that when tens of millions of doses of vaccine are weeks late, leaving a country exposed to a fairly dangerous virus, we might get something more specific than that one company was overoptimistic and another had trouble filling syringes.
In a way, this is to be expected, for most people in virology and public health recognize that our conventional mode of making vaccines is outmoded and is no match for pandemic viruses. A six-month production schedule -- six months when everything goes well -- is no match for a virus that can go global in weeks.
So one big question is whether this shortfall -- which would be catastrophic if this flu did its ugliest job on even, say, 5 percent more of the infected -- will inspire a serious move toward other strategies. Nonadjuvanted vaccines, for instance, can get to more people sort of quickly, and other vaccines in development, such as those built by via cell culture or modeling or with virus-like particles, can be made much more quickly. But how vigorously will we pursue these? There's a risk that simply because this flu is so far not killing vast numbers of people, the existing complacency about the threat of pandemics will couple with the antipathy or apathy about vaccines to leave the current inadequate system in place.. "Well, that wasn't so bad, even though the vaccines were late. The strategy worked." Combine that with the veil of proprietary secrecy over the production delays, and you get a formula not for better vaccines, but for simply trying the same strategy next time.
In short, if we care so little about the delays, and about vaccines in general, to accept that these delays were simply a bad-luck "perfect storm" (even while being to-be-expected), then we're less likely to put in place something much better for next time. The conventional egg-based vaccine approach isn't working for flu. It's too slow, too glitchy -- and apparently not terribly accountable. We've spent a lot of money and invested a lot of hope in vaccines that are getting here too late. If this holds up and is not seen as a major failure needing correction, we're missing what at this point appears to be a learning opportunity that is vital but relatively inexpensive -- if, that is, you can call thousands of deaths inexpensive.
I don't believe for one minute that the problems these companies were experiencing had anything to do with "proprietary" processes - this is simply their way of covering up manufacturing screw-ups (just as governments like to cover mistakes with "classified top secret" labels).
I also don't believe that there was nothing the CDC could have done to prevent this. While I have not researched this, I would be surprised if the CDC did not have the power the require prompt disclosure of manufacturing shortfalls or delays - for example: requiring the companies to disclose the results of their potency surveys. If the CDC does not currently have such power, they should certainly write it into the next set of similar contracts.
The whole thing sounds like a classic case of the regulator getting much too comfortable with the regulated.
I completely believe the causes of these delays are proprietary in nature; these companies will patent anything they possibly can, and with good reason. They need those secrets to make money.
What I don't understand is how they could possibly be "overoptimistic." Biological samples are notoriously finicky. Anybody who knows what they're doing should be pessimistic almost to a fault. If I'm doing lab work that tells me I'm going to get 80% return of a sample, I just assume I'm getting 50% back at most and count myself lucky if I get even that. That these companies did not operate under the same assumptions is astounding to me.
I'm dubious of the whole thing. CDC has admitted (by use of the Freedom of Information Act) that their numbers are skewed after CBS did an investigative report showing that they have overestimated the number of H1N1 cases substantially. Many people who have been told since July that they had "probable" Swine Flu did not have it- or any other flu. CDC forced states to STOP testing for Swine Flu in July. So, people who have previously believed that they had H1N1 and that they had immunity are now being told to get a vaccine anyway. A vaccine which can cause rare but serious complications such as Guilliane Barr. And which is- by the way- in short supply. What is the real story here?
Do you think we are going to start seeing adjuvant in use? Would this be a possible outcome of the "state of emergency" thingie? And wouldn't that be a good thing?
"A vaccine which can cause rare but serious complications such as Guilliane Barr." I am calling bullshit here. Please provide more information before making these assertions. Yes, that syndrome was once associated with a bad batch of vaccinations though it hasn't since. At present the chances of acquiring it "naturally" from the flu are larger then acquiring it from being vaccinated. Something anti-vax folks always forget to mention. As always if you have a history of adverse events after getting vaccinated take them seriously and talk to your doctor. Though for the rest of us the vaccine provides unambiguously solid gains and protects us and the people we love while the 'serious complications' are only a nebulous and unsupported assertion.
Back to point. I do agree that a for profit vaccination industry isn't a very good system to ensure the necessary supply. At best market forces just don't have a strong enough predictive power to induce the necessary preparation ahead of time, and at worst can result in hoarding and extortion. Likewise, if we have a particularly mild flu season that is an unambiguously good thing. Unless, you are the ones making vaccines and millions of doses go unused. We need to make the vaccine creation process much more concerned about public health and less interested profits.
"Only one, MedImmune -- the company supplying the adjuvanted FluMist product -- has come close to its promised delivery schedule."
I'm 99.99% certain FluMist does not contain an adjuvant.
"Basically they had difficulty making "acceptable" vaccine that did not contain an immune booster called an adjuvant, which is used in several countries but not the United States."
Why on earth would not adding an adjuvant be a cause for 'difficulty'?
Greg - I personally don't think we will see adjuvants used at any point with the novel H1N1 vaccine for a number of reasons. First, I'd assume Alum would be the only viable option at this point since using any other adjuvant would require numerous lengthy safety tests - and the 'pandemic' may well be attenuate by the time these studies are completed. Reformulating the already manufacture vaccine would undoubtedly add time and $. Formulating upcoming vaccine with adjuvant seems viable (and logical), yet I'd still be surprised if this happens. After listening to a joint CDC/DHHS conference, I got the feeling these organizations understand the public's irrational nonacceptance of adjuvant use. The fear that even fewer people may be willing to receive the vaccine if it contains an adjuvant seemed to be a major deterrent.
1. My bad on the FluMist: You are right, there's no adjuvant in it. It's built around a weakened rather than the killed virus used in the shots built by the other four companies, and so is not eligible for quite as many users, which is one reason the CDC ordered only some of those. Plus I understand the CDC (and some others) are generally leery of inhaled vaccines, though there is quite a range of opinion on that. I may be overlooking or forgetting other reasons for using/not using the Flumist-like product.
As to a possible switch to adjuvanted vaccines:
1. I certainly don't think we'll see adjuvanted vaccines used for H!N! in the U.S. this year, and probably not in the next couple years. Several reasons: The adjuvanted doses this year are already spoken for by other countries; you can't just take the existing nonadjuvanted doses on order and jigger them with adjuvants, for that occurs way upstream in the process; and the CDC and FDA are both leery of adjuvanted vaccines because of political and social resistance, even aside from safety concerns. I wrote about this aversion to adjuvanted vaccines in my Slate piece a few weeks back, at http://www.slate.com/id/2228700/. I don't think the debate is changed much as yet.
Thanks for writing, all.
David, thanks for the clarification and the link to your Slate article - a very nice piece indeed. Keep up the good work!
I am still terrified that we are going to get to the front of the line and they are going to say, "So sorry, we just gave the last dose to the people in front of you" :)
I was actually surfing looking for conversation about the politicization of hin1 when I found your post. Really interesting read, but scary. Thanks.
In Canada, Arepanrix(TM) H1Ni has been approved:
* Split virion (to provideH1N1 antigen)
* Inactivated: viruses are killed and partially dismantled, washed, and purified.
* Adjuvanted with AS03 and an oil-water emulsion
* AS03 contains DL-alpha-tocopherol (Vitamin E), squalene (a normal biological fat), and polysorbate 80 (anti-oxidant?)
It does contain a small amount of thiomersal. It was cultured on eggs so those allergic to eggs must avoid it.
The adjuvant has been used in other flu vaccines and enables us to make the vaccine we have protect four times as many people.
It's not approved for babies under 6 months; they depend on antibodies in breast milk, staying away from crowds, and others who have been vaccinated so as not to get sick around them.
Children 6 months to 9 years are supposed to have two half-doses 21 days or more apart. However, children over six may need only one.
Free vaccination has begun for vulnerable groups. (DAMN that universal medicare!)
Ever since the Clinton Administration federalized flu vaccine, the delivery of vaccine has drifted later into the flu season. You would think that the Obama Administration would be more concerned that this experiment in federalized medicine not turn into a "Katrina" response -- too little too late -- in the year of his health initiative. If it is the companies who have failed under their federal contract -- and from what I can tell they have not -- why has the federal response not been as swift and direct as, say, the reaction to Fox News coverage.
I certainly don't think we'll see adjuvanted vaccines used for H!N! in the U.S. this year, and probably not in the next couple years. Several reasons: The adjuvanted doses this year are already spoken for by other countries; you can't just take the existing nonadjuvanted doses on order and jigger them with adjuvants, for that occurs way upstream in the process; and the CDC and FDA are both leery of adjuvanted vaccines because of political and social resistance, even aside from safety concerns.
I may be overlooking or forgetting other reasons for using/not using the Flumist-like product.