Effect Measure

This week in swine flu vaccines

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.

Comments

  1. #1 Mark
    September 12, 2009

    Thanks, Revere, for this thoughtful and informative commentary.

  2. #2 Don Cotler
    September 12, 2009

    As a pediatrician and member of the International Conspiracy to Harm Children for Profit I am of two minds about nationalizing vaccine production. It would make mass murder more efficient, but would cut out most of the profit.
    Seriously, can you imagine the brouhaha such a proposal would provoke among all the different lunatic groups who would see this as part of their brief?

  3. #3 revere
    September 12, 2009

    Don: What I was suggesting is that Americans imagine how they’d feel if other countries decided to take control of vaccine supply by virtue of having the facilities within their borders rather than by virtue of it being an object of free market commerce (so a rich country wouldn’t have to worry where it was made). Over the years, our suggestion has always been that vaccines are not ordinarily good candidates for efficient production by a market system (there is a larger argument here I’m not making in this short comment) and that as a common good it should be internationalized via a system of (the number is only for the sake of argument) ten regional international vaccine institutes, supported by int’l contributions via the UN system or World Bank or whatever. Each would make vaccines for their region for at cost or no cost dispersal to countries in that region, each would share technologies and expertise. Their job would be to produce enough vaccine to cover any possible demand, which would mean either the ability for rapid scale up (that kind of technology is not becoming available) or gross over production that in a “good” flu year might to unused and potentially wasted. That’s not a business a drug company wants to be part of. They only want to be part of it when times are “good for them” (i.e., bad for the rest of us, as in a pandemic) and by then it’s too late.

    So, to be absolutely clear, I think the “national system” (complete sovereignty within national borders) has no use in public health and runs counter to it. But for common goods like vaccines, neither does the international “free trade” market system. Each may have their virtues in some circumstances (that’s another discussioin) but not for this.

  4. #4 concerned
    September 12, 2009

    Dr. Cotler, could you clarify your position further? Are you being sarcastic with this comment, or, are you in one of these lunatic groups?

  5. #5 Jonathon Singleton
    September 12, 2009

    Revere, “Perhaps it’s time to talk about taking common goods like vaccines out of the market system…”

    Cheers for bringing this issue up. And yes, Americans and Australians should feel utterly ashamed for their failure to ask vaccine manufacturers like CSL LTD. why they’ve left their safe and economical plant-based adjuvant on the shelf when making that 15 mcg dose of inactivated antigen swine flu vaccine. Possibly up to three people can be vaccinated with a 15 mcg dose of A/California/7/2009 (H1N1) virus antigen using Iscomatrix adjuvant — the company press release spiels and science journal studies show this plant-based adjuvant to be highly efficient. Did they even bother to see if an immune response would occur with a 5-7 mcg adjuvanted version!?!

    Anyway, onto the University of Maryland/NIH ferret study: H5N1 was not part of that study equation. We don’t know what might happen between swine and bird flu in countries such as Indonesia and Egypt.

    So, erring on the side of caution I turn to Julio Garcia Moreno MD, MSc Head, Biomedical Department Instituto de Salud FAblica de Chile and his recent ProMed pleas for a global (multi-governmental and WHO) refocus on where and when vaccines should be distributed first to hinder the evolution of pandemic strain H5N1-H1N1…

    Revere, everyone can bugger off with the derisory laughter until we have some lab studies carried out on the possibility. What IF the most sensible course of action IS Julio Garcia Moreno’s first strategy (see below), where Indonesia’s population are vaccinated BEFORE America and Australia!?!

    PRO/AH/EDR> Influenza pandemic (H1N1) 2009, animal health (05): Chile, avian (August 29, 2009)

    Excerpt: “Final report about genetic study of 1st transmission of A(H1N1)2009 virus from human to birds…

    “I think that now we are facing a new scenario where the chances of the influenza A(H1N1)2009 virus passing to birds [infected with H5N1] is not just a possibility but a reality. This forces us to think some new strategies in order to diminish the risk of [H5N1 and H1N1 co-infection in the same host, mixing existing genetic info into a deadlier transgenic strain]…

    This new [H5N1/H1N1] virus might be able to infect humans and spread [easily from person to person via evolved surface proteins which have never before] been in contact with human immunology system…”

    Some strategies to evaluate are:
    ——————————–
    1. Review the established priorities for use the new A(H1N1)2009 vaccine. In my opinion under this new scenario would be a world priority to vaccinate in 1st term the whole population in countries in which actually there is presence of the avian influenza virus (some African and south Asian countries). The vaccine is the best tool to cut the transmission of the virus among humans and therefore the chance of infecting birds…”

  6. #6 don cotler
    September 12, 2009

    Having to cope daily with the results of inefficiencies resulting from free market failures in vaccine production, I would love to see something along the lines of what you propose. I just needed to express my frustration at dealing constantly with scientifically illiterate (“educated”) people who announce that they have “done the research” and have reached conclusions about vaccines. It struck me that any such proposal would inflame anti-vaccine nuts, anti-”one world government” nuts, any variety of Luddite, generalized anti-”Big Medicine” nuts, “Obama wants to control your children’s mind” nuts, post-modern “my truth is as good as your truth” nuts, etc. etc.

    Re Concerned’s concern, it is the lunatics who think I am part of (or at least a dupe of) a large well-disciplined conspiracy. In truth, I spend a lot of time and emotion trying to explain medicine to them, against my own financial interest. (I have administered over 300,000 immunizations in my career, with no significant adverse events, and I am lucky if I break even after getting screwed by the current system.)

  7. #7 merciless
    September 12, 2009

    Forgive me if this has been covered elsewhere (I try to keep up, but…) but what is the “seasonal flu” vaccine available now? Is it H3N2? Is there any evidence that this strain is circulating, and would it be worthwhile to take it?

    The reason I ask is that it’s being hyped pretty hard right now and I’m concerned that people are going to assume that it’s for H1N1 and think that they’re covered for the year.

  8. #8 neil
    September 12, 2009

    Wow! And I thought you were going to be brief and concise..,

    Nice job!

    I’m signing up for my jab as soon as it’s available. whether adjuvanted of not..,

  9. #9 revere
    September 12, 2009

    merciless: The seasonal is the usual trivalent vaccine: H3N2 and H1N1 Brisbane strains and flu B (current strain). There is some question how well matched the H3N2 is. There is still seasonal flu out there and we don’t know what the mix will be this fall. The assumption that H1N1 swine flu will crowd out everything else may or may not be correct. We don’t know yet, and as an over 65 individual I am at risk of dying from one of the seasonal flu bugs more than those younger. Will the two interfere? There is no real data to go on, but I don’t see why they should from the standpoint of immunology, although flu always surprises us. I’ll get both.

    I don’t think there will be any or much confusion in the mind of the public. That’s one of the values of calling this swine flu. If you call it H1N1 no one knows what the hell you are talking about. When the vaccine is available I think the messaging will be very clear.

  10. #10 merciless
    September 12, 2009

    Excellent–just the info I was looking for. Thank you.

  11. #11 Curious
    September 12, 2009

    Do you think the vaccines will even be ready in time for the fall wave? Mid-October translates to at least early November by the time things are shipped and ready to distribute. (My state STILL has no seasonal vaccine, despite news reports it was “available” in August. They tell me check back in early October. For the SEASONAL vaccine.

    The spike in cases seen in this week’s Fluview is alarming. Assuming that those states were hard hit early because of school starting, that means the rest of us could see a rapid rise in cases in as few as 2-3 weeks.

    I’m not sure that this vaccine is going to do much good for fall’s first wave. And I’m angry about it — logical or no. We’ve had months to prepare, and the average American is still no better protected than they were in April. Handwashing and hope, that’s all we’ve got.

  12. #12 Jonathon Singleton
    September 12, 2009

    Revere, “The assumption that H1N1 swine flu will crowd out everything else may or may not be correct. We don’t know yet…”

    Indeed Revere, the University of Maryland/NIH research team would agree with you. Their ferret studies have shown clinical feature questions surrounding swine and Brisbane flu co-infections. That team wonder if their data is being replicated in human co-infection cases.

    I raised this subject at Crof’s Blog the other day:

    Crof’s H5N1 Blog — “Canada: Swine flu confirmed at Vancouver school” (September 08, 2009)

    http://crofsblogs.typepad.com/h5n1/2009/09/canada-swine-flu-confirmed-at-vancouver-school.html

    Jonathon Singleton said in reply to Crof (September 09, 2009)

    Edited excerpt: “Re: recent University of Maryland/NIH study which tackled this “crowding out” question and more.

    It appears as if seasonal H3N2 (A/Brisbane/10/07) [BR/10] and A/California/04/09 (H1N1) [Ca/04] flu virus strains can happily co-exist within the same infected host and exacerbate clinical symptoms. So, according to this study, maybe the Brisbane 10 seasonal strain is still kicking around out in the community and doing the co-infection dance with swine flu!?!

    Here’s the link to the Maryland/NIH study:

    PLoS Currents: Influenza — “Fitness of Pandemic H1N1 and Seasonal influenza A viruses during Co-infection (Evidence of competitive advantage of pandemic H1N1 influenza versus seasonal influenza)” By Daniel Perez, Erin Sorrell, Matthew Angel, Jianqiang Ye, et al (Aug 25, 2009)

    Excerpt: “[Using the ferret model our] studies showed that the current pandemic virus is more transmissible than, and has a biological advantage over, prototypical seasonal H1 or H3 strains…

    Our studies show that the pandemic Ca/04 virus has a clear biological advantage in replication, transmission, tropism and pathogenesis when compared to both seasonal H1 and H3 representative strains…

    However, since co-infection with the H3 seasonal strain resulted in exacerbation of clinical signs, it is important to determine whether co-infections have been associated in some of the lethal human cases.

    Surveillance should consider careful examination of clinical cases and determine whether co-infections are related to the morbidity and mortality associated with the pandemic strain.

    Based on studies in the ferret model, strong emphasis should be placed on determining whether underlying H3 infections are associated with co-infections with the pandemic strain…”

  13. #13 SusanC
    September 12, 2009

    Revere, I agree that it’s important to make vaccines available to as many countries as possible – I have been advocating about this since 2007, when I wrote about possible options to make Enough pandemic vaccines for the world.

    It’s a false choice to think that Americans (or Canadians or anybody) have to submit to risky vaccines to ‘spare antigens’ for the rest of the world. Using bioreactors in existing pharmaceutical plants anywhere in the world, the technology already exists, right now as we speak, to make tens of millions of doses a week, for countries around the world. It’s called the recombinant hemaglutinin (or rHA) vaccine.

    The company, Protein Sciences, have said to the WHO they are willing to transfer technology to developing countries. South Korea, for example, has enough capacity to make more than it needs, meaning that it can supply other countries in Asia. At least several other countries are interesting, eg Mexico and Japan. But there’s a hold-up, not because of technology nor lack of antigens, cos the global capacity is huge (see above links), but because the FDA is dragging its feet, for reasons that are obscure to me. Developing countries do not have the expertise to evaluate vaccines for licensure, so they depend on the FDA’s opinion.

    This vaccine has completed all clinical trials (see Treanor et al) and application for licensure was submitted to FDA in April 2008, ie 17 MONTHS ago. The advisory committee meeting for licensure was scheduled for this month but has been postponed to November. As far as I know, there are no outstanding technical issues, since early this year, the only issue is the FDA’s willingness to review and make a ruling on licensure.

    I repeat, this is 17 months since they filed, the the FDA has not scheduled a meeting. In comparison, Gardasil was licensed 6 months after filing. In fact, the September advisory commmittee slot has now been given to licensing of Gardasil for boys, and Cervarix, another HPV vaccine.

    Here’s my question: Do we have an urgent HPV pandemic killing people? NO WE DON’T, but the world is in need of pandemic flu vaccines. It only takes 2 weeks, after the FDA gives the nod, for countries to start making their own vaccines. But are they making this a priority? Heck, No!!

    I don’t believe therefore that it is rational or ethical, to ask Americans (or anyone) to submit to adjuvanted vaccines where we do not yet have the tools to evaluate their safety, when an alternative is sitting there ready to go, just waiting for the word.

  14. #14 revere
    September 12, 2009

    Susan: It’s only a false choice if sufficient vaccine truly exists or will exist in time for this pandemic. I have no doubgt that the technology exists to make enough antigen. The question is whether enough antigen will be made, and if not, what to do about it. If there’s more than enogh antigen to go around without adjuvant and the safety of the alternative process is at least as good as the conventional technique that’s fine. Then we don’t have to argue about it. Do yo predict that will be the case? If not, then the choice is not false but real.

  15. #15 SusanC
    September 13, 2009

    Revere,

    If there’s more than enogh antigen to go around without adjuvant and the safety of the alternative process is at least as good as the conventional technique that’s fine. Then we don’t have to argue about it. Do yo predict that will be the case?

    Yes, I do, based on the work of Fedson and Dunnill, which I have followed for the past few years.

    The vaccine is made using the well-characterized baculovirus expression system. Briefly, you take the HA gene from the flu virus, insert it into a baculovirus, which grows well in insect cells. The baculovirus makes lots and lots of the HA protein, which is harvested and used as vaccine.

    Once the initial steps, of creating the recombinant baculovirus, characterizing it, etc have been done (and they have), then you can just send this virus seed to whichever lab wants to make the vaccine, and they can grow the virus in the insect cell system. Each production cycle is only 5 days, which means first doses can be available fairly quickly.

    On the subject of capacity, according to Fedson, in this paper pandemic vaccines for H5N1,

    The existing global bioreactor capacity is approximately 2 million liters. Using conservative assumptions about production yields and bioreactor availability (only 500,000 l), it would be hypothetically possible to produce in 3 months enough doses of adjuvanted 3.75 mg rHA vaccine to vaccinate (with two doses each) 3.4 billion people;….the major obstacles would be regulatory and commercial.

    Using Fedson’s estimates, assuming 15ug per dose and no adjuvants, 500,000L capacity would make 1.7 billion doses in 3 months. I understand that discussions have been under way since May/June with various countries. One single company in Mexico has a 5,000L bioreactor ready to go, which can make (using the above estimates) 170 million doses in 3 months (but they will be available on an ongoing basis, as the production cycle is only 5 days). Another plant in South Korea has >25,000L capacity. These are the ones that I know of, more discussions have gone on with other countries.

    All that is for labs that are already using insect cell systems, which can be up and running in a couple of weeks. Labs that are using bioreactors to make monoclonal antibodies or use other cell substrates, will need some modification which may take more time.

    The other side of the argument is, even assuming the US uses adjuvants, how much antigen can they spare? If the Novartis vaccine needs 7.5ug, that is not a huge amount of dose sparing. Whatever you spare, to give to developing countries, only makes sense if they too use the adjuvanted form of vaccine. The question is, is there enough adjuvant being made? I don’t know the answer to that question.

  16. #16 revere
    September 13, 2009

    SusanC: I know this system and have posted about it. It has regulatory hurdles to pass in every country and its safety also has to be assured as does that of any vaccine and for the same reasons. The antigen has to be purified from this system (as it does from egg based ones) and also inactivated. In those many steps there are possibilities for things to get into the vaccine that could be very dangerous. That’s why vaccines are tested for safety as well as efficacy, even when thy don’t have adjuvant. So this system is not ready for use in this flu season. Maybe the next none. The world is messy. As for sparing, the adjuvanted vaccines are being trialed at 3.75 mcg and that would be a four fold increase. 7.5 is a doubling. That’s twice as many doses. That’s not negligible. Not enough, maybe, but an awful lot of people.

  17. #17 SusanC
    September 13, 2009

    Switching gear. You may recall that I was not in favor of governments taking over vaccine research, production, etc. As I find out more and more on vaccine issues, I’m now inclined to agree with you. Vaccines are an important public health tool. The choice of which kinds of vaccine to develop should be based on sound science and public health needs, not profit motivations.

    The HPV vaccines are the best example of this issue. These vaccines are marketed towards prevention of cervical cancer as an endpoint. >80% of cervical cancer deaths are in developing countries. (Agosti 2007) The incidence of cervical cancer in America is among the lowest in the world. So a vaccine developed for reduction of cervical cancer deaths only makes sense if it’s affordable to developing countries. Right now Gardasil is priced at $120 per dose x 3 doses. Agosti et al estimates that it is cost-effective in developing countries only if the price comes down to $1-$5 per dose.

    There’s a story behind this that also has to do with adjuvants. The virus-like particles (VLPs) used in HPV vaccines were developed by the National Cancer Institute (NCI) The original NCI trials compared the unadjuvanted vs alum-adjuvanted and MF59 adjuvanted versions, and found that the efficacy of unadjuvanted and MF59 was similar, whereas alum was inferior. The adverse reactions were more severe with both adjuvanted vaccines. Hence the authors concluded that the unadjuvanted vaccine was the best choice. Harro 2001, Pinto 2003), and yet eventually both licensed versions are adjuvanted (Gardasil with alum, Cervarix with AS04). Even though the FDA says the use of adjuvants have to be justified by science, that justification is absent from all the documents available in the public domain, on Gardasil. Further, in the clinical trials for Gardasil, 90% of controls were given alum, only a small group in one trial was given a true placebo saline. Cervarix is the same – the trials were conducted comparing Cervarix either with alum, or other alum-adjuvanted vaccines. The use of adjuvants os ‘control’ (I refuse to call them placebo) masks the true incidence of adverse events.

    Anyway, back to the issue of government involvement. In this case, government scientists at the NCI developed the VLPs and found the unadjvanted version the best option, but once commercial interest got onboard, decisions were made that run counter to that science. As a result, we now have costly vaccines targeted towards the LEAST at risk population but most able to pay, while the poorest women in the world who should be the REAL target of this vaccine, are all left out.

    So, yes, there’s a strong case for governments taking over vaccine development as a public health commitment. Don’t know if that will happen any time soon, though.

  18. #18 SusanC
    September 13, 2009

    The antigen has to be purified from this system (as it does from egg based ones) and also inactivated. In those many steps there are possibilities for things to get into the vaccine that could be very dangerous.

    Yes the antigen has to be purified, but no they don’t have to be inactivated, because the product is a protein, not parts of a virus. (I know you know that, but there are probably readers who don’t…)

    Yes, there are many things that get into vaccines that need to be removed. And, sometimes problems don’t necessarily lie in purification per se but in our ability to confirm that the endproduct is pure. In this case, because the product is a single protein in solution, the purity is relatively easy to determine using chromatography.

    I agree vaccines need to be tested for safety and proven safe, whether or not they have adjuvants. Every vaccine needs to be considered on its own merit.

  19. #19 revere
    September 13, 2009

    Susan: You are not producing intact flu virus with this system, but it is living tissue culture. So you have to worry about other replicating agents in the mix. The fast tracking of the egg based viruses is related to the claim that it is only a strain switch, so the other elements used in producing the antigen and vehicle aren’t different than what we’ve seen. But that isn’t true of cell culture systems, so the one you are talking about isn’t really the same in that regard.

  20. #20 SusanC
    September 14, 2009

    I know it isn’t the same. This whole discussion is in the context of antigen sparing, to produce vaccines for countries that might otherwise have no vaccines at all. Sure, the fast-tracking of the current vaccine because it is a strain-substitution is entirely appropriate – I fully support that. But it’s an entirely different level of risk when we start talking about using adjuvanted vaccines.

    What it comes down to, is 2 things: the relative risk of the seasonal formulation (low) vs adjuvanted vs recombinant vaccines. Plus what exactly are Americans being asked to choose between?

    What I’m saying is, instead of asking Americans who would otherwise be receiving the safer seasonal formulation, to agree to take the risk of taking adjuvanted vaccines in demonstration of global solidarity, wouldn’t it make more sense for the US to stay with the current plan of using the seasonal formulation, but to facilitate the licensing and technology transfer of the recombinant vaccine for countries that need/WANT it, instead?

    Whether or not the rHA vaccine is fit for licensure, the FDA should make a ruling Yes/No on it sooner rather than later. THAT is my biggest complaint. It isn’t ethical to leave the questions unanswered, when so many countries could have chosen that route – can still choose this route right now – if the licensure issue is dealt with promptly.

  21. #21 SusanC
    September 14, 2009

    Note also that the rHA vaccine licensure is NOT fast-tracking. This is based on full documentation submitted for regular licensure for seasonal use.

  22. #22 SusanC
    September 14, 2009

    A ruling on the rHA vaccine has to be made eventually. Suppose it is licensed next year, after the worst of the pandemic is over.

    What do you think people in South Korea or Japan or Mexico would feel, knowing that they had the technology to make it in time to save some of the people who died, but no vaccines were made because the US considered the licensure of this vaccine a FAR lower priority than licensing Gardasil for the use in boys??

  23. #23 Katie
    September 17, 2009

    From the cdc site:

    “Will the 2009 H1N1 vaccines that are currently recommended contain adjuvants?
    No. According to current federal plans, only unadjuvanted vaccines will be used in the United States during the 2009 flu season. This includes all of the 2009 H1N1 and seasonal influenza vaccines that will be available for children and adults in both the injectable and nasal spray formulations. None of these influenza vaccines will contain adjuvants.

    2009 H1N1 vaccines with adjuvants are being studied to determine if they are safe and effective. Experts will review these data when they are available. There is no plan at this time to recommend a 2009 H1N1 influenza vaccine with an adjuvant.”

    So will the MF59 adjuvanted Novartis cell-based vaccine be used this year or not? I don’t know why I can’t wrap my head around this. Thanks.

  24. #24 ParatrooperJJ
    September 18, 2009

    In a true global pandemic, it would not matter if a foreign country voided our vaccine contracts. There is not a country in the world that could prevent us from going and taking the vaccines from them.