Effect Measure

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.

Comments

  1. #3 Jonathon Singleton
    June 24, 2008

    Bar, ta tres for the Queensland Courier-Mail article. How do you interpret these excerpted comments?

    Do you agree with my sarcasm, “[CSR's] Mary Sontrop ceases working for the good of Oz public health and acts more like a spendthrift [WHO] PR consultant.” (see my e-listed emails contained in a previous EM posting — linked below)!?!

    Here’s more sarcasm — given Indonesian government-based public health is a basket case, why would Australian citizens (living in the next country) “fail to benefit” from a trial-tested H5N1 vaccine, performing like “body armor”, offering early first wave protection against the eventual recombined H2H-H?N? pandemic serotype which will chaos-theory spread around the world in the timeframe of a matter of weeks.!?!

    Have IQ levels dropped, or what!?!

    Courier-Mail: “CSL general manager Mary Sontrop said the vaccine, Panvax, had been approved by the Therapeutic Goods Administration, Australia’s pharmaceutical watchdog, but could only be used when the World Health Organisation declared a pandemic.

    ‘There wouldn’t be any benefit to people having the vaccine now if a pandemic hasn’t been declared,’ she said.”

    Effect Measure — Not even National Lampoon would vacation in Indonesia (Posted on: June 21, 2008 9:02 AM, by revere)

    http://scienceblogs.com/effectmeasure/2008/06/not_even_national_lampoon_woul.php#comments

  2. #4 revere
    June 24, 2008

    bar: Yes, this is the infamous CSL product that started Supari on her tear. This is like other prepandemic vaccines. The seed strain is Indonesian but Australia is not going to provide Indon any until all of Australia is taken care of, if then. Depending on timing and efficacy it may or may not help Oz but is kind of irrelevant for the rest of the world.

  3. #5 bar
    June 24, 2008

    uh, thnx. ’bout what I should’a expected of our lib/lab pollies.

    Then again, I suppose that finding enough vax for 240 million is a bit harder than for 20 mill. However even providing either tech to manufacture, or doubling our manufacturing capability of vax would have been suitable conciliatory gesture.

  4. #6 miso
    June 24, 2008

    Revere,
    I think if the SHTF there’ll be a hole bunch of unethical liberties take to get a handle on a pandemic. At least I hope so.
    It’s occurred to me a good one would be rather than prophylactic dosing health professional on antivirals, and have most of the stockpiles literally “pissed away” on the off chance they might catch something,sometime. They should be infected with live H5N1 (or H7N1 or whatever it turns out to be) and treated like the so many lab rats that went before them. It’s got to be a sure fire way of having half a chance of developing immunity; being treated from the day of infection.
    Put into perspective, it sounds a lot better than keeling over with flu like symptoms and waiting a week for test results that indicate you might have lived if you’d been treated 10 days earlier, or having to invent a time machine so when you find out your infected you can travel forward a year by which time a vacine should be available ,and then trave back a year and a month so you can jab yourself a good month before your infected. Which isn’t entirely impossible because apparently there’s a small chance the Large Hadron Collider will create time travel, and a small chance it will create a black hole that will swallow the Earth, thus providing at least two solutions to bird flu.

  5. #7 anon
    June 25, 2008

    when the vaccine proofs good (better than the
    competing products), then they may produce more
    and export it or sell licenses

  6. #8 Jonathon Singleton
    June 26, 2008

    Howdy Anon, I’m a bit surprised at your comments…

    Are you involved in the science and/or medical fields? Even if you aint, the primary issue here, Anon, is so simple even an Aussie politician can grasp the concept — timing vis a vis the case-fatality rate of whatever version of H2H avian influenza recombine-manifests!

    When a building is on fire we expect the city to send in the fire trucks, pronto… The “proof” of an emergency is apparent to all and steps are taken to minimize loss of life and property. In the event of a transgenic pathogen based pandemic, we just won’t have the luxury of time for all the usual bureaucratic blah, blahing… This needs to be done (((NOW))) before the ol’ proverbial hits the fan. If you take a quick squizz at the following excerpts of an email I sent out to my e-list last month you’ll get a picture of what script we are all acting within.

    Let me say the 1964 Rolling Stones song, “Time Is On My Side” is the total opposite of what we have…

    To: “Dr F Li, Centre for Infectious Disease Prevention and Control, Public Health Agency of Canada”

    To: “Nicola Roxon, Federal Australian Minister for Health and Ageing”

    Monday May 19, 2008

    Howdy Dr. Li and Oz Minister Roxon,

    Dr Li, I’d like to sincerely thank you and your team for the latest research analysis on A/H5N1′s CFR in humans…

    I agree with your final statement (see BMJ article below). The projected 14-33% CFR in a H2H version of a cross-species pathogen infecting six billion people in an incredibly short timeframe would, quite obviously, see between three to seven times the current American population dead. To use the current American population (300 million) as a measuring stick brings emotional clarity to this pressing global health issue. If politicians could visualize this scenario as clearly as their polling statistics, then perhaps they’d act in the here and now to prevent the “blink of an eye” planetary loss of between 900-2000 million humans!?!

    I’ve recently written on Effect Measure Blog ’bout the public need for a trivalent prepandemic vaccine (clade configuration should be an appropriate mix). This crucial point in time (here ‘n’ now window before recombined H2H-H?N? develops) should not be squandered. There’s a fundamental public health need for mass worldwide prepandemic vaccination… For further information see both my May 12 reader posting near the end of EffectMeasure’s — “Australia tries to out do the US in suppression of science” Posted on: May 5, 2008 10:18 AM, by revere @

    http://scienceblogs.com/effectmeasure/2008/05/australia_tries_to_out_do_the.php#c881947

    and CIDRAP News — Launch of WHO H5N1 vaccine stockpile still awaited (May 16, 2008)
    [http://www.cidrap.umn.edu/cidrap/content/influenza/panflu/news/may1608vaccine.html
    Excerpt: “A year after the World Health Organization (WHO) called for the development of an international stockpile of vaccines against H5N1 influenza, the stockpile has not yet materialized, the WHO said in a report released today…

    Results to date also suggest that H5N1 vaccines may protect people against strains other than the one used in the vaccine, the report says. “Animal data suggest that vaccination by human H5N1 influenza vaccines, produced from viruses of one clade, may confer cross-reactivity against H5N1 viruses from other clades and therefore may confer protection against challenge by H5N1 viruses from other clades.”

    In addition, this cross-reactivity “might indicate potential cross-protection against future emerging strains, but such coverage could diminish as H5N1 vaccines continue to evolve.”
    In March 2006, I received a positive legal email from Gloria Allred, an infamous California attorney…

    Her email concerns were focused on lawsuits vis a vis time periods — this is ironic given two facts…

    * FOI have been stalling, withholding info since the get go — FOI are legally culpable for stonewalling!

    * The primary issue concerning and justifying the corrupt WA police and medicolegal establishment’s violent 1997/8 mistreatment of me was my so called “drug induced” “delusional” belief in an impending global disaster — ie. the H2H H-this N-that transgenic pandemic…

    Due to my questioning character, I happened to be one of those who awakened early to the pandemic threat of A/H5N1.

    Since 2000, I’ve been fully cognizant of the probable consequences of accelerated horizontal gene transfer and recombination — evolutionary paradigm driving cross-species pathogens…

    Cheers:*) Jonathon

    Journal of Epidemiology and Community Health 2008;62:555-559; doi:10.1136/jech.2007.064030 Copyright � 2008 by the BMJ Publishing Group Ltd.

    Article — Finding the real case-fatality rate of H5N1 avian influenza
    By F C K Li1, B C K Choi2, T Sly3, A W P Pak4

    [http://jech.bmj.com/cgi/content/abstract/62/6/555

    Excerpt: “We suggest that, based on surveillance and seroprevalence studies conducted in several countries, the real H5N1 CF rate should be closer to 14�33%… Clearly, if such a CF rate were to be sustained in a pandemic, H5N1 would present a truly dreadful scenario. A concerted and dedicated effort by the international community to avert a pandemic through combating avian influenza in animals and humans in affected countries needs to be a global priority.”

  7. #9 Jonathon Singleton
    June 26, 2008

    Take 2 — the links stopped my comments from being posted — take the time to google the originals yourselves…

    Howdy Anon, I’m a bit surprised at your comments… Are you involved in the science and/or medical fields? Even if you aint, the primary issue here, Anon, is so simple even an Aussie politician can grasp the concept — timing vis a vis the case-fatality rate of whatever version of H2H avian influenza recombine-manifests!

    When a building is on fire we expect the city to send in the fire trucks, pronto… The “proof” of an emergency is apparent to all and steps are taken to minimize loss of life and property. In the event of a transgenic pathogen based pandemic, we just won’t have the luxury of time for all the usual bureaucratic blah, blahing… This needs to be done (((NOW))) before the ol’ proverbial hits the fan. If you take a quick squizz at the following excerpts of an email I sent out to my e-list last month you’ll get a picture of what script we are all acting within.

    Let me say the 1964 Rolling Stones song, “Time Is On My Side” is the total opposite of what we have…

    To: “Dr F Li, Centre for Infectious Disease Prevention and Control, Public Health Agency of Canada”

    To: “Nicola Roxon, Federal Australian Minister for Health and Ageing”

    Monday May 19, 2008

    Howdy Dr. Li and Oz Minister Roxon,

    Dr Li, I’d like to sincerely thank you and your team for the latest research analysis on A/H5N1′s CFR in humans…

    I agree with your final statement (see BMJ article below). The projected 14-33% CFR in a H2H version of a cross-species pathogen infecting six billion people in an incredibly short timeframe would, quite obviously, see between three to seven times the current American population dead. To use the current American population (300 million) as a measuring stick brings emotional clarity to this pressing global health issue. If politicians could visualize this scenario as clearly as their polling statistics, then perhaps they’d act in the here and now to prevent the “blink of an eye” planetary loss of between 900-2000 million humans!?!

    I’ve recently written on Effect Measure Blog ’bout the public need for a trivalent prepandemic vaccine (clade configuration should be an appropriate mix). This crucial point in time (here ‘n’ now window before recombined H2H-H?N? develops) should not be squandered. There’s a fundamental public health need for mass worldwide prepandemic vaccination… For further information see both my May 12 reader posting near the end of EffectMeasure’s — “Australia tries to out do the US in suppression of science” Posted on: May 5, 2008 10:18 AM, by revere and CIDRAP News — Launch of WHO H5N1 vaccine stockpile still awaited (May 16, 2008)

    Excerpt: “A year after the World Health Organization (WHO) called for the development of an international stockpile of vaccines against H5N1 influenza, the stockpile has not yet materialized, the WHO said in a report released today…

    Results to date also suggest that H5N1 vaccines may protect people against strains other than the one used in the vaccine, the report says. “Animal data suggest that vaccination by human H5N1 influenza vaccines, produced from viruses of one clade, may confer cross-reactivity against H5N1 viruses from other clades and therefore may confer protection against challenge by H5N1 viruses from other clades.”

    In addition, this cross-reactivity “might indicate potential cross-protection against future emerging strains, but such coverage could diminish as H5N1 vaccines continue to evolve.”

    In March 2006, I received a positive legal email from Gloria Allred, an infamous California attorney…

    Her email concerns were focused on lawsuits vis a vis time periods — this is ironic given two facts…

    * FOI have been stalling, withholding info since the get go — FOI are legally culpable for stonewalling!

    * The primary issue concerning and justifying the corrupt WA police and medicolegal establishment’s violent 1997/8 mistreatment of me was my so called “drug induced” “delusional” belief in an impending global disaster — ie. the H2H H-this N-that transgenic pandemic…

    Due to my questioning character, I happened to be one of those who awakened early to the pandemic threat of A/H5N1.

    Since 2000, I’ve been fully cognizant of the probable consequences of accelerated horizontal gene transfer and recombination — evolutionary paradigm driving cross-species pathogens…

    Cheers:*) Jonathon

    Journal of Epidemiology and Community Health 2008;62:555-559; doi:10.1136/jech.2007.064030 Copyright 2008 by the BMJ Publishing Group Ltd.

    Article — Finding the real case-fatality rate of H5N1 avian influenza
    By F C K Li1, B C K Choi2, T Sly3, A W P Pak4

    Excerpt: “We suggest that, based on surveillance and seroprevalence studies conducted in several countries, the real H5N1 CF rate should be closer to 1433%… Clearly, if such a CF rate were to be sustained in a pandemic, H5N1 would present a truly dreadful scenario. A concerted and dedicated effort by the international community to avert a pandemic through combating avian influenza in animals and humans in affected countries needs to be a global priority.”