There’s been a great deal in the news regarding the first reports on the swine flu vaccine trials, so we didn’t feel the need to be the first off the mark for something you could read anywhere (and everywhere). We still don’t have much to add, but since there was intense discussion and debate about vaccines here this week we thought it appropriate to take a look again now that there are some actual data to see if it changes things for us or not. The short answer (but typical for us) is: yes and no. First, let’s review what we think we know at this point (this is big picture; we might have missed some results or details here or there; things are happening fast and the vaccine isn’t one of our obsessions).
We have results for a few swine flu trials, vaccines made by China’s Sinovac company and international vaccine makers Novartis, CSL Ltd. and Sanofi-Pasteur. A slew of other companies are said to be about to release results soon, too. Preliminary results from Novartis and CSL (Austalia) were published in the New England Journal of Medicine this week (see links at bottom of the CIDRAP News link). Results for the Sanofi-Pasteur vaccine trial and another CSL trial were mentioned briefly in a news release by the US’s chief research scientist on infectious disease, Dr. Anthony Fauci of NIH, where more trials are being conducted. There are many issues we could talk about, but we’ll confine ourselves to the ones we raised this week regarding safety and adjuvants. The results announced this week are pertinent to that issue, since they appear to show that half as much viral antigen (and half the time) than originally thought will be needed, even for vaccines without adjuvants.
The Novartis and one of the CSL trials are the ones we know most about because of the data published in the NEJM. The Novartis vaccine is grown in cell culture, not eggs, and contains an adjuvant (MF59) that has been used and licensed in Europe since 1997 but not in hte US. Adjuvants boost the immune system’s response to the viral antigen, which allows use of less antigen (so-called antigen sparing) and possibly quicker and higher antibody responses (I again refer you to the excellent post over at Virology Blog). But being biologically active and administered to potentially hundreds of millions of people, even rare adverse events (say one in 100,000) could pile up fast. Adjuvants are therefore controversial. If we knew they were perfectly safe we’d use them because it would allow much greater vaccine to be produced with potentially better effect, but we can’t be sure because it’s not feasible to do clinical trials for rare adverse events. We depend upon post-use surveillance. Hence we are balancing the risk from the adjuvant (and in the Novartis case the use of their particular cell culture technique rather than egg technology), which might or might not be negligible, against the benefits of being able to vaccinate more people and possibly get a quicker and better response. It’s a judgment call that different national authorities have done differently. We expressed a preference that the US use adjuvanted vaccine because we know there is insufficient vaccine productive capacity to protect a large proportion of the world’s people. Because the US is the biggest player and has bought up a large share of the world’s ability to produce viral antigen, we believed it was better on balance to use a technology that put the least demand on it as possible. This wouldn’t be an ethical issue if there were an equitable rationing system, but vaccines have turned the ability to live a life free of influenza infection into a commodity and the US has the money to buy it.
What the latest trial results add to this debate is that it appears it will only take one dose of the same amount of viral antigen used in seasonal flu (15 micrograms [mcg]). Because this is a new and novel virus with respect to human experience, it was thought that it might take a higher dose (say 30 mcg) administered twice several weeks apart to achieve protection. The NEJM papers suggest that it takes only a single 15 mcg dose of unadjuvanted vaccine (CSL Ltd. egg-based) or 7.5 mcg of MF59 adjuvanted Novartis cell-based vaccine to do the trick. That’s the broad-based picture you see in the news stories, but as always, there are some nasty details still to be worked out.
First, how do we tell whether the vaccine will really protect people from being infected with flu? We can’t experiment on them, inoculating them with flu virus and comparing vaccinated and unvaccinated people. What is done, instead, is to take blood at various intervals after vaccination and test to see if there is evidence of developing antibody activity against the flu virus. If you want to know more about these assays take yourself over to Vincent Racaniello’s Virology Blog (here’s one post on the subject and here’s another) where he not only explains them but has great pictures to show you what it actually looks like when you do them. The assumption is that if you have a certain level of antibody by one assay or another you will be protected. That’s based on studies of seasonal flu over the years. But the assays measure different things and the levels needed to protect against one strain might be different than another. As of now we don’t have good data for the pandemic strain, so we are using information from seasonal strains. We think these assays give us good information, but one thing we see is that they produce different results for the same vaccine. In the case of the Novartis adjuvanted vaccine, 7.5 mcg of viral antigen produced assay values we believe indicate sufficient for protection in 76% when measured by the hemagglutination inhibition and 92% when measured by the microneutralization test after 21 days (various other doses and timings were also done, so this is just illustrative of some of the issues). Novartis also tested single doses of adjuvanted vaccine at 3.7 mcg and unadjuvanted vaccine at 7.5 mcg, but have yet to release the results. Meanwhile, a single-dose of CSL egg-based unadjuvanted vaccine at 15 mcg produced a protective antibody titer in 97% after 21 days. While CSL also used two different assays, I was only able to find data for the hemagglutinin inhibition response, but I may have missed it. However it is noteworthy that about a third of the volunteers already had protective levels (by HI) before vaccination, presumably because there was a lot of swine flu circulating in Australia when the trial was conducted. So the excellent response in the CSL trial might have had a substantial priming component.
These were both small trials, so the relative absence of adverse events is neither surprising nor particularly informative of what might happen when we ramp up to hundreds of millions of vaccinees. Soreness at the injection site and headache and occasional fever were the most serious effects, but affected a significant fraction of volunteers, although not thought to be more than for seasonal vaccines. There was a suggestion that the adjuvanted (Novartis) vaccine had more such events, however, which is quite likely if the adjuvant is biologically active.
Meanwhile more trials are going on. NIH’s Fauci, in a news release had this to say:
We are encouraged by reports that are now emerging from various clinical trials of 2009 H1N1 influenza vaccines, conducted by various vaccine manufacturers. We expect additional companies to announce their preliminary trial results shortly. The early data from these trials indicate that 2009 H1N1 influenza vaccines are well tolerated and induce a strong immune response in most healthy adults when administered in a single unadjuvanted 15-microgram dose. We congratulate the companies on these trials, which are an important part of the ongoing worldwide effort to develop vaccines to protect the public from 2009 H1N1 influenza.
The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, also is conducting clinical trials of 2009 H1N1 influenza vaccines, produced by Sanofi Pasteur and CSL Limited. The NIAID trials are testing two different dosages (15 micrograms versus 30 micrograms) and evaluating the immune response to one and two doses of these vaccines. More than 2,800 people are participating in ongoing NIAID trials of these vaccines.
We are pleased to note that preliminary analyses of early data from the NIAID trials align with the recently announced findings and those to be announced imminently by other companies in that both vaccines studied induced what is likely to be a protective immune response in most adults following a single dose in the same amount (15 micrograms) used in seasonal flu vaccines. Specifically, in blood samples obtained 8 to 10 days after vaccination:
Among healthy adults who received a single 15-microgram dose of the Sanofi Pasteur vaccine, a robust immune response was measured in 96 percent of adults aged 18 to 64 and in 56 percent of adults aged 65 and older.
Similarly, among healthy adults who received a single 15-microgram dose of the CSL Limited vaccine, a robust immune response was measured in 80 percent of adults aged 18 to 64 and in 60 percent of adults aged 65 and older.
Additional data from the NIAID trials are forthcoming. However, on the basis of these strong early data, our results are consonant with other reports that a single 15-microgram dose of unadjuvanted 2009 H1N1 influenza vaccine is well tolerated and induces a robust immune response in healthy adults between the ages of 18 and 64. For adults aged 65 and over, the immune response to 2009 H1N1 influenza vaccine is somewhat less robust, as is the case with seasonal influenza vaccines. (NIH News Release)
Let’s return to our opinion that the US should use adjuvanted rather than non-adjuvanted vaccine because that would save more people around the world, albeit at some additional (possibly non-existent) risk to the US population. The mathematics of net benefit clearly support most adjuvanted vaccines where the potential risk of adverse event is on the order of 1 in 100,000 or even 1 in 10,000, the latter much higher than any ever reported. But the new results also show that the world might have access to much more viral antigen than previously thought. That makes it more difficult for us to feel confident about what the right balance is. Of course that decision won’t be made on ethical grounds. It will be a political and economic decision.
But that doesn’t mean we can’t or shouldn’t have an opinion about it or keep silent about it. This won’t be the last time (alas) that a rich country will use up a disproportionate amount of resources that could have saved many other people. It is often difficult to put yourself in someone else’s shoes, but I suggest to my fellow (American) citizens they consider the following scenario. Most of the viral antigen we are counting on (because a vaccine country signed a contract with us) are made outside US borders. What if the country where the vaccine is physically produced decides to nationalize the vaccine facility and service its own citizens and its political allies and friends first, leaving what’s left for the rest of the world at a later time. That could happen in a really bad pandemic. Since we don’t have a sufficient vaccine production capacity to provide for our population, it wouldn’t matter what contracts we signed. We’d be like any other country that didn’t have the foresight to build vaccine plants rather than factories to make the more profitable pills for erectile dysfunction.
Perhaps it’s time to talk about taking common goods like vaccines out of the market system.