Thursday, July 30, 2009

Novartis: We have done no testing for the carcinogenicity of MF59

At the 12/2008 FDA-NIH meeting on how to study novel adjuvants, Novartis scientist (Novartis owns the MF59 adjuvant) Dr. Novicki made the following statement:
"Carcinogenicity--we have done no testing for the carcinogenicity of MF59 adjuvant or any of our preventive vaccines. We haven't done it and we don't plan to." (See page 391.)
And if that wasn't reckless enough, DHHS Secretary Sebelius has since given Novartis a liability waiver through the PREP Act for injuries their swine flu vaccines and adjuvants may cause, as long as Novartis lacks prior knowledge of the products' dangers.

Are you wondering what else they may not be testing for?

Wednesday, July 29, 2009

More Novel Adjuvants for the Swine Flu stockpile

HHS Purchases Additional H1N1 Vaccine Ingredients--July 13, 2009

(Thanks to Bloomberg News)


Bulk Vaccine


Bulk Virus Concentrate/FFF

Bulk Oil and Water Adjuvant

Sanofi Pasteur
























That means the Department of Health and Human Services has now purchased $698 million dollars' worth of oil-in-water (squalene-containing) adjuvants for the H1N1 Swine Flu pandemic. ($283 million was spent earlier for these adjuvants.) Having expended more than 2/3 of a Billion dollars on these products, it is virtually assured they will be used.

How much do we know about them? At a meeting called by FDA and NIH's NIAID in December 2008 to discuss how to perform studies to determine whether the new adjuvants were safe, there was relatively frank discussion by the speakers. Dr. Pulendran noted:
"if you take stock of the major vaccines that have been made since Edward Jenner's smallpox vaccine in 1798 right through to the first recombinant vaccines to be licensed, say, for example, the Hepatitis B vaccine, what I find very
interesting about this slide is that despite the success of many of these vaccines, we really do not understand the mechanisms by which they stimulate immune responses...(p. 61)
Dr. O'Hagan of Novartis pointed out:
MF59 activates 891 genes... MF59 was the most potent activator and it induced transcription of chemokines, cytokines... (p. 114-115)
According to Dr. van der Laan:
"From a pharmacological point of view, we feel, as the European authorities, that there is a lack of knowledge of mechanism of action. There is a lack of dose response relationships. A lot of studies are done with only one, maybe two dosages, a lack of combination studies with different endpoints.

And most is the focus on immunological effects and there is hardly any idea about cardiovascular or CNS effects. You can imagine that if you have a vaccine leading to the release of cytokines, that there might also be cardiovascular effects... (p. 277)"

What do their remarks mean?

Vaccines, even older ones, work through poorly understood mechanisms. That is why it is very hard to predict their side effects, and effectiveness, in advance. Not until they are given to many thousands or sometimes millions of people are the adverse effects discovered.

Furthermore, MF59 induces a very strong immune response. It activated more genes than any other adjuvant tested. The activated genes are not all immune response genes. In fact, scientists don't know what most of the activated genes really do. That is why scientists cannot predict what effects the adjuvant will have on humans with different genetics and ages.

A powerful immune reaction may be excellent for the elderly, whose immune systems weaken considerably with age. Remember, MF59 has only been licensed overseas for use in flu vaccines for those over 65 years of age. Presumed safety in this age group cannot be extrapolated to the young. There is no evidence of MF59's safety in young adults, and especially in children.

At the FDA-NIH meeting, Dr. van den Bossche characterized scientists' fears about the new adjuvants:
"But what we really want to avoid is that the use of adjuvants would enhance local reactogenicity or even worse, would also enhance systemic reactions. So what we want to avoid is severe reactogenicity. And we are especially, I think, scared of a kind of generalized, unspecific stimulation of innate immune cells breaking tolerance, for example, things that may lead to immune pathology."
From FDA's Dr. Gruber:
"Now safety is always primary but safety is relative. It is not absolute. So in determining whether a vaccine product is safe, one has to look at the indicated target population, the nature of the product, the indication, and the circumstances under which the vaccine will be used...(p. 260)
And because of safety concerns, the law in the Code of Federal Regulations under the IND regulations requires that adequate information about the pharmacological and toxicology studies that have been conducted or that should be conducted for the vaccine or adjuvanted vaccine need to be available... (p. 261) And, again, to remind you, the law also states that an adjuvant shall not be introduced into a product unless there is satisfactory evidence that it does not effect adversely the safety or potency of the product." (p. 262)
The problem with this statement is that by invoking the Public Readiness and Emergency Preparedness Act of 2006 and the Emergency Use Authorization of Bioshield legislation, these laws that protect us have been dispensed with. The law he referred to, tells FDA what evidence of safety is required in order to license a medicinal product.

But the laws we are currently operating under, invoked for the Swine Flu pandemic, authorize use of untested, unlicensed products on the entire population. All in a very compressed period of time.

Thus there will not be enough time to discover any adverse events that take months or years after vaccination to show up, such as autoimmune disorders or excessive allergic responses. The entire population will already have gotten its shots before such side effects appear.

Furthermore, the recent history of vaccines includes a few spectacular failures. A few caused increased susceptibility to the disease they were meant to prevent. Licensed animal vaccines have caused cancer at the injection site in cats, and autoimmune thyroid disease in dogs. Some have contained bacterial or other contaminants.

Monday, July 27, 2009

Underlying assumptions about a swine flu immunization program should be explicit and shared with the public

The 1978 National Academy of Sciences (NAS) report on the 1976 Swine Flu Vaccination Program points out that a large number of assumptions going into the program were never acknowledged or critically examined. For example, the report lists the following assumptions that were made when the program was conceived:
high-yield eggs, one dose per person, high efficacy, unparalleled acceptance, favorable publicity, sustained congressional support, wide private involvement, adequate state operations, three months to complete vaccinations, no useful stockpiling, no liability legislation, few (if any) opportunity costs, etcetera.
And the report's authors emphasize:
In short, we advocate a comprehensive definition and review of assumptions everyone can see and weigh before decision and remember after. The review thus should be public.
Today, it is unclear what assumptions policymakers have made about the Swine Flu program. In 1976, President Ford was told an epidemic resembling the 1918 Pandemic was lurking, and he was pressed into acquiescing to the program with limited information, on the basis of "expert" advice.

In the context of the 1976 Swine Flu Program, the 1978 NAS report calls attention to a major problem with expert advisory panels:
Panels tend toward “group think” and over-selling, tendencies nurtured by long-standing interchanges and intimacy, as in the influenza fraternity. Other competent scientists, who do not share their group identity or vested interests, should be able to appraise the scientific logic applied to available evidence. In medicine, as in law, there are rules of evidence by which argument can be tested.
Expert medical and scientific opinion, obtained from outside the beltway and devoid of personal agendas, is of critical importance. Policymakers are unpracticed at dealing with the breadth of issues to be considered in large vaccination programs, and with attendant risk/benefit analysis. Can they, and we, learn the lessons of 1976?

Sunday, July 26, 2009

Legal immunity set for swine flu vaccine makers: What are the implications?

AP Medical Writer Mike Stobbe got a swine flu vaccine scoop--yet the news is four weeks old. It turns out that DHHS Secretary Sibelius has not only given immunity to the makers of Tamiflu and Relenza for injuries stemming from their use against swine flu. She also granted immunity to future swine flu vaccines and "any associated adjuvants," which was published in the June 25, 2009 Federal Register. Here is the start of his story:

The last time the government embarked on a major vaccine campaign against a new swine flu, thousands filed claims contending they suffered side effects from the shots. This time, the government has already taken steps to head that off.

Vaccine makers and federal officials will be immune from lawsuits that result from any new swine flu vaccine, under a document signed by Secretary of Health and Human Services Kathleen Sebelius, government health officials said Friday.

Since the 1980s, the government has protected vaccine makers against lawsuits over the use of childhood vaccines. Instead, a federal court handles claims and decides who will be paid from a special fund.

The document signed by Sebelius last month grants immunity to those making a swine flu vaccine, under the provisions of a 2006 law for public health emergencies. It allows for a compensation fund, if needed...
However, the compensation issue is more difficult than portrayed by Stobbe. The special vaccine court to which Stobbe refers applies only to specially designated vaccines, excludes most adult vaccines, and swine flu is not a designated vaccine for which compensation can be paid.

The 2006 Public Readiness and Emergency Preparedness Act (PREPA) allows the DHHS Secretary to invoke almost complete immunity from liability for manufacturers of vaccines and drugs used to combat a declared public health emergency. PREPA removes the right to a jury trial for persons injured by a covered vaccine, unless a plaintiff can provide clear evidence of willful misconduct that resulted in death or serious physical injury, and gets permission to sue from the DHHS Secretary. There has been no government funding of its potential compensation mechanism, to date. Furthermore, a PREPA declaration explicitly shields "government program planners" who arranged for the liability waiver.

Pharmaceutical companies making swine flu vaccine today may have demanded immunity from liability before agreeing to begin a crash program to manufacture H1N1 vaccine for the government. According to a 1978 report by the National Academy of Sciences, something similar happened with the 1976 swine flu program:

... all manufacturers made plain that they would not insure themselves, not even temporarily. Instead they put off plans to bottle their vaccine; pending legislation they would keep the stuff in bulk. Each week’s delay in moving from bulk to bottles assured at least as much delay in starting inoculations. Thus ended hopes of immunizing anybody in July or even August...

Behind Merrell’s firmness, there almost certainly was fear of the intentions of the casualty insurers. In May it was no secret that at least some major firms wanted to steer clear of swine vaccine. As early as April 8 Merck had been warned by its primary insurer that coverage for swine vaccine was “considered” not “feasible … at virtually any price.” So Merck's President had written Mathews and everyone else in sight.

Merrell, then about to switch insurers (for unrelated reasons) is reported to have been told by its new one something of the same sort at about the same time. We do not know precisely what was made of this, where in Merrell’s management. We do know that the issue was reviewed again, in June, by the insurer with the same result, a “no.” But we assume that Merrell’s counsel knew in May what the insurer had already warned in April. However that may be, it shortly would turn out that all insurers saw the swine flu program much alike: not for them.

Here is the problem: once the PREP Act is invoked to shield manufacturers from liability, the pharmaceutical firms have no financial incentive to make the safest product, and have a negative incentive to test it for safety. As long as they do not deliberately harm consumers of the product, they will not be liable for damages.

Are you following this argument closely? In order to avoid having prior knowledge of possible harm to users of the product, for which they could be found liable, it is in the manufacturers' best interest to know as little as possible about adverse reactions caused by their product.

Thus manufacturers can be expected to perform minimal testing, as they have been incentivized by PREPA to avoid learning of potential harms related to their product. The rush to manufacture and administer new vaccines serves two purposes: it provides an excuse to avoid adequate testing, as well as providing rapid vaccine availability. For example, see this Bloomberg article, "Glaxo to Limit Tests of Flu Vaccine, Citing Urgency."

On the other hand, France, which has ordered vaccines from Sanofi, Glaxo and Novartis AG, sees no reason at this point to ask vaccine makers to shorten or skip clinical trials, Health Minister Roselyne Bachelot-Narquin said at a news conference.

It is worthwhile to go back and consider the reason for passing PREPA in 2006: fear of an avian flu pandemic, in the event the avian flu virus mutated to enable person-to-person spread. Avian flu then had a 70% death rate. Faced with such a potentially devastating disease, it perhaps made sense to create legislation to permit rapid deployment of drugs and vaccines without adequate testing, and issue a liability shield for those involved in the process.

But the H1N1 flu has only caused 353 US deaths (as of July 31),though CDC estimated over one million Americans had been infected (as of June 30). Instead of 70%, H1N1's death rate is under 0.03%. Therefore, this virus in no way justifies the risks the population is being asked to take: receiving vaccines, and perhaps experimental adjuvants, which their manufacturers have been encouraged not to test, with no prospect of compensation for illness or death that might result.

Friday, July 24, 2009

Damn the Data! Full Speed Ahead

There are many federal advisory panels, often comprised of those with vested interests. This panel did as expected, calling for precipitous vaccine approval. The Wall Street Journal reports:
In the U.S., a federal advisory panel said the FDA should move ahead to approve or license the new H1N1 vaccine without waiting to receive data from clinical trials to test its safety and efficacy. The government and vaccine makers plan to start human studies of the H1N1 vaccine in the U.S. in the coming weeks, but the first-look data from those studies won't be given to the FDA until September.
From Gannett:

But the FDA told its scientific advisers it could finish the red tape of licensing much of that vaccine well before the use-it-or-not decision is made — because it's brewed exactly the same as regular winter flu vaccine, merely using the new swine influenza virus, part of the common H1N1 influenza family, as the chief ingredient. Companies just have to take the normal steps required for each year's regular winter flu vaccine, such as proving the inoculations are manufactured appropriately.

Taking the same path now will save some important time because "the virus is ahead of us," said FDA vaccine chief Dr. Norman Baylor. This "is not a rubber stamp. We do need to review some data to give us some comfort that that vaccine will provide some benefit and that it's manufactured properly."

... Make no mistake: Vaccines containing immune-system boosters called adjuvants are not candidates for the easier strain-change approval, the FDA said. Flu vaccine with this extra ingredient is widely sold in Europe but never has been sold here, and there's little information about their safety in young children or pregnant women. While both adjuvant-free and adjuvant-added swine flu vaccine is being tested in the U.S. and abroad, using it outside of those studies would require a completely separate government decision.

FDA appears unwilling, currently, to take the bigger risk of approving novel adjuvants, which have not been tested in at-risk populations, without data. But the risk that our federal regulatory agencies are willing to take is equal to the risk these agencies took in 1976, when no new vaccine adjuvants were used. In 1976, 6-8 times as many Guillain Barre Syndrome (autoimmune paralysis) cases occurred as would have occurred by chance alone, after vaccination.

Although somewhat reassuring, this is not good enough. Yearly flu vaccines have traditionally been approved each year with very abbreviated testing, compared to other vaccines. Now swine flu vaccine is being pulled through that same loophole, because government officials have a precedent, which makes doing so (bureaucratically) easy.

They need to remember the Guillain Barre precedent also.

The 1978 National Academy of Sciences report on the 1976 Swine Flu vaccination program, from which 2009 policymakers could learn a lot, contains the following:

"Decision-making for the swine flu program had seven leading features. To simplify somewhat, they are:

  • Overconfidence by specialists in theories spun from meagre evidence.

  • Conviction fueled by a conjunction of some preexisting personal agendas.

  • Zeal by health professionals to make their lay superiors do right.

  • Premature commitment to deciding more than had to be decided.

  • Failure to address uncertainties in such a way as to prepare for reconsideration.

  • Insufficient questioning of scientific logic and of implementation prospects.

  • Insensitivity to media relations and the long-term credibility of institutions."

Vaccine Development, Targeting, and Use of Unapproved Products

This HHS chart indicates that vaccine will be distributed in early November, after which "monitoring effectiveness and safety" begins.

Here is an excellent H1N1 swine flu links page from the National Library of Medicine.

This DHHS/DHS document explains the plan for priority targeting of (pandemic) influenza vaccinations.

According to FDA:

Through an Emergency Use Authorization (EUA), the Project BioShield Act of 2004 gives FDA authority to make promising drugs, biologics, and devices quickly available in emergencies.

This Act allows FDA, based on an evaluation of available data, to

  • authorize the emergency use of unapproved or uncleared medical products
  • authorize the unapproved or uncleared use of approved or cleared medical products

The authorization may remain in effect for the duration of the declaration justifying the emergency use (up to one year). The declaration may be terminated prior to one year or renewed at the end of one year. FDA can revoke an EUA if, for example, the criteria for issuance are no longer met.

Soon after HHS declared a nationwide public health emergency on April 26, 2009, FDA issued authorizations for the emergency use of certain influenza medicines, diagnostic tests, and certain personal respiratory protection devices.

Government Purchasing Activity for H1N1 Antigens and Adjuvants

US DHHS Orders for Bulk Supply of 2009 H1N1 Influenza Vaccine Antigens and Squalene-containing Adjuvants


Bulk Vaccine Antigen

Oil-In-Water Bulk Adjuvant


$150 million

$139 million


$ 38 million

$144 million

Sanofi Pasteur

$191 million

CSL Biotherapies

$180 million


$ 90 million


$649 million

$283 million

Tuesday, July 21, 2009

Great information on the 1976 Swine Flu Vaccination Program

I am aware of two very useful sources of information on the 1976 swine flu vaccine fiasco. Both are available in full on-line.

The first is a short article published in the Journal of the American Medical Association in 1996, written by Maurice Hilleman, PhD. Hilleman was America's pre-eminent vaccinologist until his death 5 years ago. He led vaccine research at Merck for decades, and had a reputation for frankness.

In 1978 the National Research Council (NRC) of the National Academy of Sciences produced a 150 page report on the program: The Swine Flu Affair: Decision-Making on a Slippery Disease.

The NRC interviewed virtually everyone involved. The report reads like a thriller, as the vaccine program developed unstoppable momentum despite liability hurdles, election considerations and the total disappearance of the swine influenza epidemic months before vaccinations commenced.

These papers are required reading if you want to understand the policy undercurrents of the swine flu vaccine program today, and what policymakers hope to avoid repeating.

Calls to vaccinate for swine flu without clinical data/LA Times

The LA Times' Rosie Mestel wrote about the timeline for swine flu vaccine production July 20:
Five companies are at work producing the H1N1 vaccine right now. Testing is starting this month--and by month's end, an advisory committee will meet to decide who in the U.S. is likely to be first in line for a shot.

But it takes a while get the results of these tests. "If we wait, we can't do vaccination until November," says Dr. John Treanor, chief of infectious diseases at the University of Rochester, N.Y., in the WebMD article. "If the pandemic flu follows the seasonal-flu pattern with the bulk of activity in January through March, fine. But if we see this second wave coming in September, we might be faced with the decision to do vaccinations without clinical data."
However, Dr. Treanor may not be the best person to advise on vaccine safety. He was one of five researchers who shared responsibility for a 1,565 subject anthrax vaccine clinical trial with CDC from 2002-2007, and his Rochester group vaccinated approximately 260 civilians. One in seven of those enrolled experienced a severe adverse event during the trial, but it was not halted. CDC and the investigators have still not released any detailed safety data from the trial, while military anthrax vaccinations continue.

Treanor may not feel the availability of clinical data are critical when deciding on a mass vaccination program; but I don't think the public shares this view. Especially when we have the lesson of the 1976 swine flu vaccine program to teach us about the need to establish vaccine safety before vaccinating millions of Americans.

The Australians are not so bold as Dr. Treanor:
"I think it's important for the public to know that they're going to get a safe and effective vaccine," Andrew Pesce, president of the Australian Medical Association, told Sky News television. "No one will give anybody brownie points for putting out a vaccine that didn't work or caused harm."

Sunday, July 19, 2009

Swine Influenza Pandemic: Important Questions and Answers

Q: How virulent is this virus?
A: It appears to be about as deadly as usual flu viruses--but with the major caveat that younger people are hardest hit. CDC reports 263 deaths and 40,000 confirmed cases in the US, but expects that over 1 million have been infected. The UK reported its 15th death on July 10, with 9,718 confirmed cases. Reuters reported this was the first entirely healthy person with H1N1 in the UK to have died. But on July 17, the UK announced there have been 55,000 cases and 29 deaths.

This virus probably spreads more easily than recent flu virus strains, since few people (mainly those in their 50s or older) appear to have any pre-existing immunity. There is no evidence the virus has become more virulent since the pandemic began.

CDC announced that pandemic flu activity has dropped for the third week in a row on July 17, though cases are apparently climbing across the pond.

Q: How can it be effectively treated?
A: I have seen no study of the effectiveness, if any, of Tamiflu (Oseltamvir) or Relenza (Zanamivir) against Swine H1N1. According to the manufacturer's label, Tamiflu reduced the duration of (non-pandemic) influenza symptoms by 1.3 days compared to patients receiving placebo in prelicensure clinical trials. Whether it can save lives remains an open question. From the London Times:
"The most comprehensive scientific assessment of Tamiflu and Relenza, produced by the Cochrane Collaboration this year, found that though they were effective in preventing or curtailing symptoms and complications of seasonal influenza, it was currently impossible to gauge their effectiveness in a pandemic, and little evidence to suggest that they would stop its spread. But it still recommended their use. For the time being, they’re the best we’ve got. "
CDC, with the most extensive data on Swine H1N1 deaths of any country, has still not informed clinicians of the causes of death and effective treatments.

Fortunately, the Australian government has provided this guidance to their clinicians.

Q: Will Swine H1N1 develop resistance to Tamiflu?
A: Probably. There are already a few reports of resistance from 3 countries. The different H1N1 virus that caused most of last year's influenza cases, and was predicted to return (the 2009-10 flu vaccine was formulated against it and two other viruses) was virtually 100% resistant to Tamiflu, and resistant to Relenza as well.

After receiving a course of Tamiflu, from 1.3% to 8.6% of post-treatment viral isolates showed Tamiflu resistance, according to the Tamiflu label. So resistance is likely to spread soon.

Q: Does anticipation of Tamiflu resistance make the need for vaccine more urgent?
A: Not really, since we do not know if Tamiflu is helping to prevent serious illness and deaths.

Q: Isn't a vaccine a necessity?
A: A safe and effective vaccine against this new pandemic virus would be wonderful, especially for high-risk individuals.

The problem with a vaccine is that governments want one available very quickly. The UK expects to have some vaccine available by the end of August (yes, that is only 6 weeks from now). The US hopes to begin vaccinations in late September or October. But achieving that kind of speed creates a host of problems that are being discussed by vaccine and public health professionals, outside public view.

If you want a new vaccine, designed against a never-before-seen virus, you will not know how effective and safe it is until you test it. But with the virus upon us, every week of testing sets back its use by a week. If the vaccine were to undergo the usual duration of testing, it might not be available for years. That is not acceptable to WHO and other public health agencies.

If you want at least a billion doses (which would correspond to one dose per person in the wealthy countries of the world) it will take a number of months for production under the best of circumstances. But today's circumstances are not the best. The CDC-supplied attenuated virus is producing a disappointingly low pandemic flu vaccine yield.

But there is a way out. It involves using novel adjuvants along with vaccine antigens. These adjuvants stimulate the immune response considerably. You require a lot less vaccine antigen with a new adjuvant (an estimated 1/5th as much), and there are even hopes that the immunity induced will be broader and stronger than with standard vaccinations. The immunity might even be effective against a mutated, more virulent virus. There is just one catch: the adjuvants that could induce such strong immunity may not be safe. Or they may be unsafe in certain patient populations, such as infants and/or those genetically predisposed to autoimmunity.

In December 2008, only 7 months ago, FDA and NIH held a 2-day meeting to discuss the types of research that could be done to evaluate the safety of such adjuvants. Then, unexpectedly, the H1N1 pandemic hit. And the plans that were slowly progressing to respond to an avian flu epidemic in the far future suddenly switched into prime time, absent the desired safety data.

Two new adjuvants being prepared for a pandemic flu vaccine (ASO3 and MF59) contain "oil in water" emulsions. The oil is squalene, which is a cholesterol precursor. However, when injected, squalene may cause arthritis or autoimmune effects. The US government recently promised to purchase 119 million doses of ASO3 and MF59, made by Glaxo-Smith Kline and Novartis, for new pandemic flu vaccines.

This is a very complex subject and I will be writing a lot more about it in the next few days.

Flu-associated deaths in children under 18--CDC

Deaths in the under 18 age group from flu-associated illness, per CDC:

The following table presents the total number of deaths in children in the United States associated with influenza infections for the past four years:

Year _____ Deaths
2008-9 _____ 9
2007-8 _____ 89
2006-7 _____ 77
2005-6 _____ 46

CDC's influenza vaccine for seasonal (non-pandemic) influenza, 2009-10

Useful facts regarding the standard (non-swine) flu vaccine: advice from CDC:
  • 84% of the population is now advised annual vaccinations
  • All children 6 months through 18 years of age are advised annual vaccinations
  • Vaccination is recommended for “All persons who want to reduce the risk of becoming ill with influenza or of transmitting it to others”
  • Vaccine last year was 44% effective
  • An oculorespiratory syndrome, typically mild, has been linked to influenza vaccination, and it may or may not recur upon subsequent flu vaccinations; its pathogenesis is uncertain
  • The flu vaccine for the 2009-10 season will contain the same H3N2 and H1N1 (NOT the swine H1N1) antigens as were in the past year's vaccine, but will have a new influenza B component
  • Most flu last year was H1N1, and all tested H1N1 strains were resistant to Tamiflu, but sensitive to adamantanes. Tested H3N2 and Influenza B strains were sensitive to both Tamiflu and Zanamivir.

Saturday, July 4, 2009

H1N1 update: Australia/Hong Kong/US

While CDC has not committed to a strategy beyond Tamiflu (to which some viral strains in Hong Kong have resistance), Australia faces a major H1N1 outbreak, as the southern hemisphere winter just began. But mathematical modelling suggests the US has already experienced 1 million H1N1 cases.

On May 17, Australia moved to a new national health alert level, called “protect,” to focus on the early treatment of those vulnerable to [severe illness from] the flu, including pregnant women, people with respiratory disease, heart disease, diabetes and obesity. And on July 2, Australia's Health Minister, Nicola Roxon, reassured parents that swine flu does not pose a greater danger to children than seasonal flu.

Separately, Sydney immunisation specialist Robert Booy said swine flu was likely to kill twice as many children over the next 12 months as regular influenza. The professor estimated 10-12 children could die from the virus, compared with five or six from normal flu strains in a typical year.

In the US, normally under 100 children die each year as a result of seasonal influenza infections. To prevent an estimated 100 excess deaths (this is a very rough estimate), up to 75 million children might receive a vaccine containing novel adjuvants, for which testing was limited.

Friday, July 3, 2009

H1N1 vaccines with novel adjuvants being developed for potential mass use

The US government has contracted with at least 5 pharmaceutical manufacturers to develop and produce H1N1 vaccines, using a variety of platforms and manufacturing methods. This is an excellent approach, since at this point no one knows which will succeed and how long it will take to obtain desired quantities of vaccine.

A novel feature of the two H1N1 vaccines being developed by companies Novartis and Glaxo-Smith Kline is the addition of lipid-containing adjuvants to boost immunogenicity and dramatically reduce the amount of viral antigen needed. This translates to much faster production of desired vaccine quantities. UPDATE: The US does not plan to use novel adjuvants in its swine flu vaccines. However, Canada and some other nations do plan to use them. The US will retain its stockpile of approximately 150 million doses of MF59 and ASO3.

Each company has its own proprietary adjuvant, acquired in each case at high cost and intended for the high-stakes business of rapidly producing vaccines for novel pandemics or biological warfare threats.

Novartis' adjuvant is named MF59, and Glaxo's is ASO3. We know they work beautifully to strengthen vaccine efficacy. But how safe are they?

That is a very difficult question to answer. Novartis claims MF-59 has been used safely by over 40 million people. However, FDA has not seen fit to approve even a single US vaccine that contains these novel adjuvants.

One European vaccine contains MF59, and two European vaccines contain ASO4, which is a Glaxo adjuvant related to ASO3. Fluad (with MF-59) is only licensed for use in the over-65 population. This age group responds weakly to standard flu vaccines, and whether standard flu vaccines actually reduce flu cases in this age group is controversial. So a stronger vaccine may be indicated for this group. And as we age, we are much less likely to develop autoimmune disorders, so potential autoimmune side effects should also be less in this age group.

However, in the 12 years since Fluad was approved in Italy for older adults (and later in the EU, but not by every country in the EU) no other vaccine containing MF-59 has been licensed... even though MF-59 has been used in a large number of vaccine trials. Virtually all the scientific literature on this adjuvant has been produced by scientists working for the manufacturer, precluding an unbiased assessment of safety at this time.

Glaxo's ASO4 is used in Fendrix (a Hepatitis B vaccine). Fendrix may only be used for people with end stage kidney disease. Patients on kidney dialysis have a high rate of Hepatitis B infection, and a weak immune system. So they are good candidates for an especially potent vaccine against a disease to which they are highly susceptible, and these recipients are unlikely to develop autoimmune complications.

Cervarix is a vaccine directed against several strains of human papilloma virus (HPV), licensed in both Europe and Australia, which contains ASO4. It is difficult to assess Cervarix' safety at this point in time, as data are limited. It is worth noting that FDA has delayed giving Cervarix a US license twice.

The June 19, 2009 Science magazine discusses use of these "next-generation," antigen-sparing adjuvants for an H1N1 pandemic. It quotes Norman Baylor, director of FDA's Office of Vaccine Research and Review, who noted that antigen-sparing strategies benefit populations, not individuals. "You have to think about those trade-offs," Baylor said.

Thursday, July 2, 2009

National Academy of Science forms committee to review the science of FBI's anthrax investigation

The National Academies today announced its committee membership to review the FBI's scientific analysis of anthrax. In an unusual move, the NAS has issued a 20 day comment period in which the public may dispute proposed committee members on the basis of bias.

Why was the NAS committee formed? The first mention of such a committee was made by FBI Director Mueller at a House Judiciary Oversight Committee hearing last September. I attended the hearing. Mueller only brought up the subject of a National Academy of Science investigation to sidetrack his Congressional questioners. Here is what I wrote at the time:
... responding to Rep. Nadler's question of whether the FBI would cooperate with an independent investigation, Mueller attempted to confuse the issue of an independent investigation, saying FBI was requesting this from the National Academy of Sciences (NAS). However, the NAS will only be asked to review FBI's "microbial forensic" science. (FBI's M.O. is to keep trotting out the genomics, no matter what question is asked.) And NAS didn't even know they were going to get this gig until today's hearing, suggesting NAS' study might just be a bone thrown to the committee to head off a truly independent investigation of the letters case.
The NAS will determine whether FBI's genomics work used acceptable science. I certainly hope it did, given the national security implications if it didn't, let alone the time and expense to complete the FBI-sponsored research program.

However, the very best the committee and FBI can do with all the scientific data is to determine whether the progenitor anthrax used in some of the anthrax letters came from a flask used by deceased scientist Bruce Ivins. Yet over 100 other people also had access to this flask, and might have been involved.

Therefore, what this committee finds will be entirely tangential to who sent the anthrax letters. To solve that problem requires old-fashioned police work, which includes developing a logical theory of the crime. Means, motive, opportunity and evidence will then assume their rightful places in this case.

Better Info on H1N1: Cidrap at U. Minnesota

Here is a compendium of very useful info on H1N1, both for clinicians and the public. It appears to be regularly updated. Cidrap has gathered its information from WHO, CDC and other sources.