Vaccines are the safest kind of medicine, aren't they?

You may wonder why I keep harping on inadequate testing and safety concerns. In addition to my experience treating patients who became ill following vaccinations, I have reviewed medical literature on vaccine safety. There are many stories of vaccines that appeared safe, but were later found to be dangerous. The Edmonston-Zaghreb "high titre" measles vaccine, designed to give immunity to infants at the age they are most susceptible to a bad outcome from measles infection, is one such story.

Children died at higher rates overall, in a number of countries, after receiving this measles vaccine compared to an earlier measles vaccine. Yet twenty years ago, this was the measles vaccine recommended by the WHO for children most at risk from measles. WHO later pulled its recommendation, but infants received this vaccine for several years before the problem was discovered.

No, this is not the killed ("KMV") measles vaccine of the 1960s I discussed earlier. That one caused a worse disease than measles once you were exposed to measles. This one increased the death rate from diseases other than measles. No one ever explained why. So the same 'mistake' could happen with other vaccines, since we don't know what caused the problem for either of these bad measles vaccines. With this in mind, I need sufficient assurance of a vaccine's safety and effectiveness before prescribing or recommending it.

Vaccine science is still in its infancy. Vaccines are all derived empirically: scientists don't really know which ingredients will give the desired result, so they just test various prototypes till one looks 'good.' Conversely, they cannot tell which vaccines will turn out to be 'bad' until the vaccines have undergone a lot of testing.

It is relatively easy to see how effective a vaccine will be in terms of antibody levels (though the antibodies we measure do not always predict true immunity to infection). You just measure the level of antibodies.

It is much harder to test safety. You don't know ahead of time what side effects will be caused by the vaccine, so you have to consider every adverse event that occurs after a vaccination as a possible side effect. However, statistics tells us that some adverse events will appear to occur at higher than expected rates following vaccination, but do so randomly, unrelated to causality. So regulators tend to ignore many adverse events that occur at high rates, assuming they are statistical "blips." You would need to observe large numbers of people for long periods of time to discover which were the real adverse reactions, and this is not done in prelicensure vaccine studies, and almost never done thoroughly in postmarketing surveillance.

Furthermore, the CDC's role in vaccine safety has been criticized by many (including the National Academy of Science) due to its conflict of interest in being responsible for promoting vaccine uptake as well as assessing vaccine safety.

A few adverse reactions are taken very seriously: those that are well known to be caused by vaccines. These include, for example, Guillain Barre Syndrome and brachial neuritis (nerve impairment near the site of the injection). Because they are rare and severe conditions, when they occur after a vaccination people notice.

Might asthma be caused or worsened by vaccines? It is a common illness and may result from autoimmunity. Even though hospitalizations for asthma occurred statistically more often in soldiers after anthrax (according to the Institute of Medicine here and here, but denied by military researchers) and smallpox vaccinations (soldiers "were 2.24 times more likely to be hospitalized for asthma and 2.77 times more likely to be hospitalized for autoimmune diseases" than controls in the year after anthrax and smallpox vaccinations were given, with statistical significance), no targeted study has been undertaken by any civilian federal agency to further investigate these results. And medical professionals, in general, do not believe vaccines can cause such frequent and severe adverse effects.

Illnesses that occur at many times the baseline rate after vaccination are likely to be identified as a vaccine adverse event. Rotashield vaccine caused over 20 times more intussusception than expected...but still remained on the market about 11 months. It probably caused other gastrointestinal side effects, but CDC's study of the data was not conclusive. UPDATE: And its replacement, RotaTeq, causes the same problem but is still on the market.

If, for example, the incidence of diabetes increased by a factor of 2 or 3 (instead of 20) after a vaccination, it would probably be missed given our current methods of surveillance.

The bottom line is that for most illnesses, the type of research that would resolve whether a vaccination contributed to or caused a specific illness, and in what percent of cases, has never been done.

Here is the WHO report on the Edmonston-Zaghreb high titre measles vaccine:

Wkly Epidemiol Rec. 1992 Nov 27;67(48):357-61.

Expanded Program on Immunization (EPI). Safety of high titre measles vaccine.

Unexpected results suggesting decreased survival when compared with standard titre vaccine administered at 9 months of age have been found in some field studies evaluating the performance of high titre measles vaccine. Analytical difficulties have arisen because the studies were not specifically designed to measure survival. Nonetheless, careful analysis of the results from all of the high titre vaccine trials showed decreased survival of high titre vaccine recipients, in areas with high background mortality rates, compared with recipients of standard measles vaccines at 9 months. No systematic biases could be found in the studies to explain these differences. Statistical analysis of these data suggested that the findings were unlikely to be attributable to chance alone. The panel recommended that high titre measles vaccine derived from the original Edmonston measles vaccine isolate should no longer be recommended for use in immunization programmes. Further post-licensure field studies of new measles vaccines should take into account the results of these studies. Additional detailed epidemiological studies in populations that have received high titre vaccines and their controls were encouraged.

PIP: A WHO group recommended in October 1989 that health workers in countries where measles is a significant cause of death for infants under 9 months old use the high titer Edmonston-Zagreb (EZ) measles vaccine for 6-month old infants, or as soon as possible thereafter, instead of the standard titer vaccine at 9 months. In 1990, reports from Senegal and Guinea Bissau showed that infants receiving the high titer measles vaccine before 9 months old were dying at a faster rate than those who received the standard titer vaccine at 9 months of age. These reports precipitated a WHO consultative meeting in February 1991 where participants reviewed the data in question. They considered the data to be inconclusive and recommended that countries continue to use the 1989 guidelines. Other issues later emerged causing WHO to reconvene the working group to reexamine all the safety immunogenicity, and efficacy data of the high titer measles vaccines in infants under 9 months old. Participants at the October 1991 meeting found that a link between the high titer measles vaccine and decreased survival was consistent in the 4 studies with high background infant mortality (relative risk = 1.25; p = .05), but such an association did not exist in the countries with low background infant mortality, suggesting that the vaccine had a multiplicative effect. In 3 of the 4 studies, girls were more likely to experience greater reduced survival than boys (p .02). In all 4 studies, the dose of the vaccine was a leading factor linked to reduced survival. The EZ vaccine was more immunogenic than the Schwartz vaccine at 4-6 months, particularly when maternal antibodies were present. The participants examined a mathematical model based on the submitted data and it indicated that the high titer vaccine would provide only a marginal benefit. They concluded that immunization programs should no longer use the EZ vaccine and that no more field trials of this vaccine should occur.

What do PREPA and EUAs mean for public health officials?/ Iowa's Asst Attorney General

Thanks to Eileen Dannemann for obtaining this memo from Iowa's Assistant Attorney General. It includes a very clear explanation from DHHS explaining the Public Readiness and Emergency Preparedness Act, Emergency Use Authorizations and Emergency Declarations in the context of H1N1 flu. Appended to it are a few additional comments from the Iowa AG's office.

This confirms all I have said about how PREPA precludes access to the legal system for injuries (unless willful misconduct can be proven) and how EUAs potentially allow mass use of products which may have had no human testing whatsoever.

What triggers these emergency laws to become active? All you need is the "potential" for a disease to cause a threat to national security. [Tell me how the Swine Flu is affecting national security, please... It isn't, obviously... The statutory bar for invoking these laws is set way too low.]

Medscape and Dr. John Bartlett provide US swine flu vaccine comparisons

How much mercury? Contraindications? Dosing? It's here in a simple format. And systemic reactions rates are reported to be 45%, said to be the same as for seasonal flu vaccines. (Why, if this vaccine only includes one third as much antigen, would adverse reaction rates be the same? Not sure if this is based on old seasonal flu data or new H1N1 data.) Bartlett errs slightly here, when he says there are 140 Guillain Barre cases per week in the US. The rate is 1.3/100,000/year or about 80 per week. Here researchers at Oxford note that Guillain Barre cases peak in the winter and early spring, which happens to be shortly after flu vaccine season. Coincidence? Confounding?

Another BU researcher catches the bug he is studying/Boston Globe

This week it was Neisseria meningitidis--which can rapidly kill (and spread). The affected grad student diagnosed himself. Last time (2004) several researchers at BU developed tularemia, a less acute illness. The diagnosis took longer, the disease was less likely to spread, but notifying the authorities took 6 months.

The problem is that you can't run a risk-free or mistake-free lab. People get stuck, or people inhale bugs, and sometimes they get sick. But this is another lab-acquired infection from the university with the rusting Biosafety Level 4 lab (the "National Emerging Infectious Diseases Laboratory")... the lab with the NIH environmental impact statement that presumed serious accidents didn't occur. A report by the National Academy of Science on NIH's risk assessment found it "not sound or credible."

During World War II, when the US opened labs studying very dangerous pathogens, we knew enough to site them on offshore islands, like Plum Island off NY's Long Island, and Horn Island off the Mississippi coast. Was that an excess of caution? Well, can you be too cautious with these bugs?

Sixty years later we throw caution to the winds. NIH wants an animal pathogen lab sited in the heart of the livestock industy, in Manhattan, Kansas. And an NIH-sponsored human pathogen lab is sited in the middle of Boston. The risk assessments are laughable, and GAO notes plenty of problems here, here and here, as recently as one month ago.

UPDATE: Thanks to Kobutsu Malone for pointing out that there have been over 100 accidents at 44 high containment labs reported to the government since 2003, many still under investigation.

Will our hubris undo us?

Vaccine delay? Give the government some credit

The feds have done a lot right in terms of swine flu vaccine production. While they are receiving criticism right now, it's only fair to note the things that have been done well.

At the beginning of the epidemic, with lots of deaths in Mexico, the government decided to procure enough vaccine for all who wanted it, as fast as possible, and give it out for free. Had this epidemic been as deadly as first feared, we would all be grateful for those decisions.

Anticipating the difficulties of vaccine production, and the slowness of the hens' egg process, the government decided to use a number of strategies and companies for vaccine production. It chose to order a mix of live vaccine (faster, cheaper production), cell culture-grown vaccine (faster production) and hens' egg production (tried and true, though slower). Had one process gone very well, and if the epidemic had been more deadly, more vaccine made by the fastest method could have been obtained to speed availability.

Five companies were given vaccine contracts. This would have (and has) resulted in at least some timely vaccine successes.

Novel adjuvants were purchased: enough for the whole country. Had the virus been very deadly, an adjuvant would have expanded the (injectable) vaccine supply by at least a factor of four.

When it turned out the virus wasn't all that bad, the US government wisely chose not to use adjuvant, knowing this would slow down vaccine production, but would add a significant measure of safety. This was done despite calls from WHO to use adjuvants, and despite decisions by most other developed countries to include them in swine flu vaccines.

UPDATE: Dr. Margaret Hamburg, FDA Commissioner, "defended the agency's decision not to use an additive that could have stretched swine flu vaccine supplies" at the Reuters Health Summit on November 12. More from Reuters:

"Adjuvanted vaccines contain an additive to boost the immune system response and need less of the active ingredient than the unadjuvanted types approved by the FDA.

But Hamburg said they have not been widely tested and that the agency did not want to risk using them when standard vaccines worked well with a single dose.

"Had the shape of epidemic or the characteristics of the virus and the disease required it, we would have moved toward an adjuvanted approach," she said.

"Europe took a little bit more of a risk. Yes, there was experience with an adjuvanted vaccine but it was really only used in the elderly and there wasn't experience with that vaccine in other populations, including pregnant women and children."

Last but not least, despite loud calls for more and faster vaccine availability, the feds have not rushed out a poorly manufactured product. Think that never happens?

Bacterially contaminated flu vaccine from England was about to be distributed in the US in 2004 when the UK Medicines and Healthcare Products Regulatory Agency (not the FDA, which had averted its eyes to the problem) pulled the manufacturer's license. Remember how we lost half the flu vaccine supply that year? Then the same problem recurred the next flu season.

Want to read a scary timeline of how the US public nearly received this potentially deadly, contaminated vaccine? FDA denied it had been warned by UK officials of the problems weeks before the license was pulled. Yet the Liverpool plant was notorious for problems. (I personally returned vaccine delivered to my office free (by the state) from this same factory, after reading the FDA's inspection report of its failures.)

The company at fault, Medeva, then Chiron Corp, was later purchased by Novartis. Novartis has the current contract for half the US swine flu vaccine supply, and again, there are apparently significant problems causing delays.

The agencies responsible for vaccine regulation and testing are now taking the time they need to get this right. Injection bypasses all the body's protective mechanisms, and the material injected needs to be "the good stuff." Safety and quality must trump convenience and expedience.

This is our dress rehearsal for a really serious pandemic. Let's learn from this how to do it better next time. The US could have done it a lot worse.

Postscript: This post may surprise some readers, but what I find necessary is the ability to balance benefit and risk. If a disease is very virulent, you may need to take more chances with the remedies. With swine flu, a relatively mild pandemic, there is little justification to take big risks on prophylactic measures.

UPDATE (Nov. 17 NY Times): "At a hearing before the Senate Committee on Homeland Security and Governmental Affairs, representatives of the Centers for Disease Control and Prevention, the Department of Health and Human Services and the Department of Homeland Security argued that they were right not to put immune-boosting adjuvants in the vaccine even though that could have quadrupled the number of doses available now..."

Anthrax investigation still yielding findings: Chemical composition of spores doesn't match suspect flask/Nature

This is an important short piece from Nature (online February 25, 2009) that I missed last February. It explains why the anthrax letter spores did not come directly from Ivins' flask: they incorporate metals not found in Ivins' spores, and were therefore grown under different conditions. Their progenitors probably did come from the flask, but dozens and possibly hundreds of scientists had access to samples from that flask.

Furthermore, the Bacillus subtilis contaminant present in the letters has not been matched to the strain found in Ivins' lab. The FBI speculates it might have come from another lab at Fort Detrick, but has not yet identified any lab that has it. The case against Ivins just gets weaker.

The deadly bacterial spores mailed to victims in the US anthrax attacks, scientists say, share a chemical 'fingerprint' that is not found in bacteria from the flask linked to Bruce Ivins, the biodefence researcher implicated in the crime.
The Federal Bureau of Investigation (FBI) alleges that Ivins, who committed suicide last July, was the person responsible for mailing letters laden with Bacillus anthracis to news media and congressional offices in 2001, killing five people and sickening 17. The FBI used genetic analyses to trace the mailed spores back to a flask called RMR-1029, which Ivins could access in his laboratory at the US Army Medical Research Institute of Infectious Diseases (USAMRIID) in Fort Detrick, Maryland.

At a biodefence meeting on 24 February, Joseph Michael, a materials scientist at Sandia National Laboratories in Albuquerque, New Mexico, presented analyses of three letters sent to the New York Post and to the offices of Senators Tom Daschle and Patrick Leahy. Spores from two of those show a distinct chemical signature that includes silicon, oxygen, iron, and tin; the third letter had silicon, oxygen, iron and possibly also tin, says Michael. Bacteria from Ivins' RMR-1029 flask did not contain any of those four elements.

Two cultures of the same anthrax strain grown using similar processes — one from Ivins' lab, the other from a US Army facility in Utah — showed the silicon-oxygen signature but did not contain tin or iron. Michael presented the analyses at the American Society for Microbiology's Biodefense and Emerging Diseases Research Meeting in Baltimore, Maryland.

The chemical mismatch doesn't necessarily mean that deadly spores used in the attacks did not originate from Ivins' RMR-1029 flask, says Jason Bannan, a microbiologist and forensic examiner at the FBI's Chemical Biological Sciences Unit in Quantico, Virginia. The RMR-1029 culture was created in 1997, and the mailed spores could have been taken out of that flask and grown under different conditions, resulting in varying chemical contents. "It doesn't surprise me that it would be different," he says.

The data suggest that spores for the three letters were grown using the same process, says Michael. It is not clear how tin and iron made their way into the culture, he says. Bannan suggests that the growth medium may have contained iron and tin may have come from a water source.

Hard to tell apart

The meeting offered scientists who collaborated with the FBI during the investigation an opportunity to share detailed data. The analyses will eventually be published in peer-reviewed journals, the FBI has said.

Jacques Ravel, a genomics scientist at the University of Maryland School of Medicine in Baltimore, described his team's efforts to find genetic differences between various cultures of the Ames strain, theB. anthracis strain identified in the anthrax letters. At first, the team was surprised to find that the DNA sequences of a reference Ames strain and Ames samples from the investigation, such as bacteria isolated from the spinal fluid of the first victim, were exactly the same. "It was kind of a shock," says Ravel.

For help, the researchers turned to variants found by a team at USAMRIID. Patricia Worsham and her colleagues had noticed differences in shape, colour and rate of spore formation even within a single anthrax culture. Ravel's team identified the genetic mutations associated with four variants and developed an assay for one of them, called Morph E. Researchers at Commonwealth Biotechnologies in Richmond, Virginia, and the Midwest Research Institute's Florida Division in Palm Bay created assays for three other variants.

The FBI then used that arsenal of tests to pin down the origins of the anthrax letters, matching the mix of genetic variants in the mailed spores to Ivins' RMR-1029 flask. "It has the genetic signatures that identify it as the most likely source of the growth," says Bannan.

Ravel also sequenced the genome of a Bacillus subtilis strain that was found in one of the letters. That sample did not match a B. subtilis strain found in Ivins' lab, says Bannan, but the bacterial contamination still could have come from somewhere else in Ivins' institution.

The FBI has asked the National Academy of Sciences (NAS) to convene an independent panel of experts to review the anthrax investigation data. The academy is still in the process of drawing up a contract with the FBI that lays out an agreement to perform the study, says NAS spokeswoman Christine Stencel.

Does the Vaccine Matter? The Atlantic

Thanks to Shannon Brownlee and Jeanne Lenzer, well known health journalists, for this erudite piece on the limitations of epidemiological data for flu vaccines and antiviral drugs. They are brave women to tackle and publish this piece: kudos!

A new GAO report on FDA's reliance on surrogate endpoints (such as using antibody levels generated by a vaccine to demonstrate effectiveness, instead of measuring cases of disease prevented) provides part of the explanation for why we don't know nearly enough about the drugs and vaccines in the US pharmacopeia.

Lost in Transmission — FDA Drug Information That Never Reaches Clinicians

This NEJM Article points out that, although, "Drug labels are written by drug companies, then negotiated and approved by the FDA," still, "information gets lost between FDA review and the approved label."

What often gets lost is data on harms due to the drug. Several examples are included, and it turns out that two popular drugs for insomnia actually didn't prevent patients using the drugs from having insomnia, although you wouldn't learn this from their labels. This article is an important read about drug labelling and drug regulation.

H1N1 swine flu vaccination in children

Parents are concerned about the best way to protect their children, and are asking whether to vaccinate them. Parents have to make their own risk/benefit decisions. I hope the following is helpful:

1. Do you feel comfortable enrolling your child in clinical trials? At this point in time, the swine flu vaccine program in children is equivalent to a clinical trial. The only published study of any swine H1N1 vaccine in children is from China, and we don't know if their data can be extrapolated to other countries.

2. Safety data from the China study are rudimentary, and efficacy was assessed only with antibody levels. So, for that vaccine (similar but not identical to vaccine used in the US, Canada and Europe) we lack information on how well it prevents cases of flu. Experts don't even know if one or two shots are needed for children under 10. As of October 31, the WHO's Strategic Advisory Group of Experts acknowledged that data on that age group was "limited and more studies are needed."

3. In adults, the best level of protection from seasonal flu vaccines (when the vaccine strains are a good match to circulating flu viruses) is about 70%. Younger children do not achieve this high a level of protection. A rough estimate for the amount of protection you should expect from the vaccine, assuming it works well, is a 50% to 70% reduction in swine flu infections.

In studies sponsored by the U.S. National Institute of Allergy and Infectious Diseases (NIAID), 8 to 10 days after receiving a 15 microgram dose of an inactivated vaccine that contains proteins from the novel H1N1 virus, 76% of the older children had a “robust” antibody response. But in those children between 3 and 9 years old, the same immune response was only seen in 39% of vaccinated kids, and it dropped to 25% in children 6 to 35 months.

4. If vaccinating, avoid injected vaccines that contain thimerosal (50% mercury).

5. We don't yet know if the live swine flu vaccine will be virulent for people with immune compromise. If your child will be in contact with others on cancer chemotherapy, high dose steroids, radiation therapy, etc., I would avoid live vaccines.

6. There is no published information about the safety or effectiveness in children of any live (inhaled) swine flu vaccines at this time.

7. The Canadian vaccine package insert states, "There is very limited experience with AS03-adjuvanted H5N1 vaccine in children between 3 and 9 years of age, and no experience in children less than 3 years of age or in children and adolescents between 10 and 17 years of age."

8. One US vaccine's (Sanofi-Adventis, used at my institution) package insert indicates that adverse reactions to one flu vaccine were evaluated in 2003-4 in (only) 31 children aged 6 through 36 months, and (only) for 3 days after each of two doses. Clearly these data provide little useful information. There isn't much more for older age groups.

9. I found it interesting to learn (in Science magazine) that only 3 countries recommend seasonal flu vaccinations in children: the US, Mexico and Finland.

Possible hidden hazards of mass vaccination against new influenza A/H1N1: have the cardiovascular risks been adequately weighed? (Abstract)

Med Microbiol Immunol. 2009 Oct 23. [Epub ahead of print]

Bhakdi S, Lackner K, Doerr HW.

Institute of Medical Microbiology and Hygiene, University Medical Center, Augustusplatz, 55101, Mainz, Germany, sbhakdi@uni-mainz.de.

Programs for vaccination against the new influenza A/H1N1 targeting many hundred million citizens in Europe and the USA are to be launched in the fall of this year. The USA is planning to employ a non-adjuvanted vaccine, whereas European nations are opting for inclusion of MF59, the adjuvant contained in an alternative seasonal flu vaccine, or the related adjuvant AS03 that is contained in a recently developed H5N1 vaccine. We draw attention to unappreciated hazards of using adjuvanted vaccine in Europe. Evidence from animal experiments in conjunction with clinical epidemiological data indicates that, quite irrespective of cause, stimulation of the immune system may accelerate atherogenesis. Application of adjuvanted flu vaccines to individuals at risk may therefore aggravate the course of underlying atherosclerotic vessel disease with all the clinical consequences. The same may hold true for other widespread diseases that are propelled by deregulated immune mechanisms. Safety trials conducted to date have not specifically taken these possible side effects into account, and unexpected serious adverse effects thus may follow in the wake of a general vaccination program. A prudent consequence would be to establish careful survey systems alongside with mass application of new adjuvanted vaccines, or to hold mass vaccination in reserve for use only in situations of true need, such as would arise with the emergence of a more virulent new H1N1 virus strain, or to use non-adjuvanted vaccines in individuals who are potentially at risk for adverse side effects.

Non-US swine flu vaccines mock the vaccine approval process

I apologize for ignoring this subject until now. Celvapan is the Baxter non-adjuvanted swine flu vaccine that is being used in many countries outside the US. It has no thimerosal. It is not grown in eggs, but instead is grown in tissue culture using Vero cells. This is a major advantage to people who have allergies to egg. But it is a new technique for influenza vaccines, one for which there is limited data. FDA is also concerned about the amount of residual Vero cell DNA in vaccines.

European regulators (EMEA) have approved new swine flu vaccines based on what they call "mock up vaccines." What appears to have occurred is that new swine flu vaccines were approved on the basis of earlier trials of bird flu (H5N1) vaccines, which used the same adjuvants, or which used cell culture techniques. EMEA's website (page dated April 29, 2009) discusses this subject. Per EMEA, both Celvapan and Pandemrix (GSK's ASO3-adjuvanted swine flu vaccine, which does contain thimerosal) are listed as "mock-up vaccines" on the EMEA website, indicating that the names of older, bird flu vaccines that have undergone clinical trials were retained for the new H1N1 swine vaccines.

Here is how the process is described by Marie-Paul Kieny of WHO:

In the last couple of years, manufacturers in the European Union registered “mock-up” or prototype H5N1 bird flu vaccines as nobody knows which H5N1 strain might become a pandemic strain. Manufacturers made clinical batches of an H5N1 vaccine with virus stocks from China, Indonesia and Viet Nam. They carried out clinical trials and submitted the results to the regulatory authorities who said the vaccines were fine. They are not allowed to sell H5N1 vaccines, since there is no H5N1 pandemic, but they can use the same procedure to make H1N1 pandemic vaccine. That way they can get a licence in a few days. This is another way vaccines can be licensed without clinical trials, while still ensuring safety on the basis of what is known about influenza vaccines.

Because the clinical features of bird flu (50-70% mortality) are so different from swine flu, and the viruses are quite different, using clinical trial data from so-called "mock-up vaccines" designed for H5N1, to support approval of H1N1 vaccines, makes a mockery of the drug regulation process. Note that some or all unadjuvanted bird flu vaccines required 90 mcg antigen, and 2 doses, while unadjuvanted swine flu vaccines require only 15 mcg antigen and one dose. Although seasonal flu vaccines retain their names as strains change yearly, retaining the same names for both bird and swine vaccines engenders confusion as well.

Here, EMEA provides its pandemic influenza preparedness plan. Pent-up preparedness has demonstrated itself a force to be reckoned with.

FDA plans (dated June 26, 2009) for safety evaluation of Swine Flu Vaccines

Here is an FDA briefing document for the Vaccines and Related Biological Products Advisory Committee meeting of July 23, 2009. It lays out the plan that has been followed since then. The plan involved very limited safety data collection before starting vaccinations, and a detailed plan for obtaining data on adverse reactions after vaccinations have been given.

Although scientifically sound, and apparently meeting FDA's need for "adequate" safety data, the glaring problem with this plan is that it will fail to identify significant vaccine problems (such as development of chronic autoimmune conditions) until after tens or hundreds of millions have been vaccinated. Excerpts follow from "Regulatory Considerations Regarding the Use of Novel Influenza A (H1N1) Virus Vaccines." [The italics and color are mine--Nass]

Section 5.1.6. Safety Monitoring:
Subjects should record age appropriate local and systemic reactogenicity for seven days after each vaccination. In addition, unsolicited adverse events, serious adverse events (SAEs), and deaths should be assessed for 21 days after each vaccination. Subjects should be followed for 6 months after the second vaccination for assessment of SAEs, deaths and new onset chronic medical conditions. If the study included evaluation of investigational adjuvants, subjects should be followed for 12 months after the second vaccine dose for occurrence of SAEs, deaths and new onset chronic medical conditions. For studies that include evaluation of antigen formulated with an investigational adjuvant, we recommend safety laboratory evaluations at baseline and at early and late time points post-vaccination (e.g., days 7 -10, and 21).

5.1.7 Endpoints

Safety: For each antigen dose and age group:

• The incidence of solicited local and systemic events within 7 days of each
vaccine dose
• Occurrence of unsolicited adverse events, serious adverse events (SAEs) and
new onset chronic medical conditions throughout the entire study, including
the 6-12 month follow-up period after the last dose of study vaccine

6.0 Post Marketing Evaluation:

FDA and CDC together with other agencies in the Dept. of Health and Human
Services (DHHS) are working to strengthen their ability to rapidly detect and
evaluate potential safety signals following administration of novel influenza A
(H1N1) virus vaccines. At the time of initial use of these vaccines there will be limited data from clinical studies evaluating safety. In addition, there is a possibility that some vaccines may be used under EUA (see Section 4.0).
Because of these considerations, as well as the 1976 swine influenza vaccine
experience, a number of methods to enhance surveillance for adverse events
following administration of novel influenza A (H1N1) vaccines will be utilized.

Current plans are to monitor adverse events through reports to the Vaccine
Adverse Event Reporting System (VAERS), as well as through diagnoses and
related data in the Vaccine Safety Data (VSD) link system, the Department of
Defense (DoD), Centers for Medicaid and Medicare Services (CMS), the
Veterans’ Health Administration (VHA), and other population based
(MCO/HMO) health care organizations. DHHS is coordinating these activities.
One challenge is linking adverse event data with vaccine administration data and DHHS is exploring ways to improve the link between vaccine receipt and adverse
event data.

FDA, CDC and their contractors are developing data mining tools, daily reports
designed for novel influenza A (H1N1) vaccines, and vaccinee cards with vaccine
and adjuvant details, including the manufacturer, lot numbers and date of
administration, as well as “how to make a VAERS” report” information to
enhance adverse event reporting.

FDA and CDC are planning safety surveillance systems which adapt to the
various scenarios of public/private payment and administration of vaccines. Both
agencies are working with states and on a national level to prepare multiple safety
surveillance systems, which could be adapted to study sub-populations (e.g.,
young children, adolescents, pregnant women and the elderly) and to respond to
the epidemiologic data identifying which populations should be targeted for early
vaccination. Furthermore, FDA is also developing international collaborations for
vaccine safety surveillance (standard case definitions, safety surveillance studies,
communication, and risk management activities). FDA will be working with
manufacturers and government agencies to coordinate surveillance plans. Given
the limitations of clinical trial data prior to vaccine utilization, post-marketing or post-EUA surveillance studies are critical to evaluate safety and effectiveness of novel influenza A (H1N1) vaccines.

From the US government's "Federal Plans to Monitor Immunization Safety for the Pandemic H1N1 Influenza Vaccination Program" comes the following statement, a tacit acknowledgement that determining vaccine safety will require plenty of time:

"... efforts have been made to enhance safety systems for H1N1 monitoring. The primary intent of these safety enhancements is to accelerate the availability of safety data to inform the immunization program, health care providers, and the public. Despite these efforts, there will inevitably be a time delay between when safety signals arise and when science is available to inform assessments of whether such signals are due to the vaccine or temporally related coincidental events that are anticipated. The time that is required for such determinations is primarily dependent on the incidence of the health event under investigation, how the health event is diagnosed and reported to large-linked databases, and the magnitude of the risk that is being explored. Ultimately, the safety profile of the vaccine needs to be considered in the context of the benefits of vaccination, which includes the disease epidemiology and the vaccine effectiveness. Rapid scientific exploration of the safety and effectiveness of the vaccine, a transparent process for such evaluations, and rapid and ongoing communications are important for ensuring optimal policy decisions and public confidence in the immunization program. "

Prior Approval for ASO3-Adjuvanted Vaccines?

I was asked if any other vaccines have been approved that contain ASO3. The answer is yes, and no.

No licensed US vaccines have ever contained this adjuvant. I am not aware of its presence in licensed vaccines used in any other countries, prior to the H1N1 adjuvanted vaccines.

However, ASO3 was approved by the European Medicines Agency (EMEA) for a BIRD FLU (H5N1) vaccine. Actually, it was approved for use in two bird flu vaccines in Europe: a "prepandemic" vaccine, called Prepandemrix, and a pandemic vaccine, Pandemrix (same name as GSK's new and different swine flu vaccine). A Canadian briefing paper said it was also approved for use in Asia.

I blogged about so-called prepandemic vaccinations once before. What is a prepandemic vaccine? You might well ask.

Remember, those in the business of threat assessment and pandemic planning have to find threats and develop responses to them. That is what they are paid to do. (The 8 year old Department of Homeland Security has 200,000 employees, for example. Threat assessment and response is very big business.)

BARDA (the Biomedical Advanced Research and Development Authority) is a new federal agency within HHS whose job is to support the research, development and procurement of such medical products that can serve as the response. BARDA was created to deal with bioterrorism initially, so it has a quasi-military, "can do" flavor, compared to our public health agencies, which have more grounding in clinical medicine and risk-benefit analysis. BARDA buys the pandemic vaccines.

Even though there never was a bird flu epidemic, considerable planning and expenditures went into responding to the possibility of one. One result was the production of huge quantities of bird flu (aka H5N1 influenza virus) vaccines, both in the US and elsewhere. GSK discusses its novel adjuvants and development of bird flu vaccine here.

Bird flu did kill over 50% of those infected. So our governments bought us vaccines. But they didn't know if the vaccines would work. That uncertainty helped make the case for adding a novel adjuvant. The adjuvants were billed as expanding the immune coverage provided. If they didn't work against whatever bird flu happened to emerge, they were still supposed to provide some initial immunity, such that a second, better targeted vaccine would generate much higher levels of antibody, specific to the right virus, than if there had been no initial vaccine.

Of course, this claim was theoretical, since until a bird flu epidemic occurred, you wouldn't know whether the old bird flu vaccines would provide any immune advantage--but it gained traction nonetheless.

The next idea to gain some traction was that since a bird flu epidemic would be devastating, maybe countries should just go ahead and give their citizens a first dose of bird flu vaccine to get us all primed in advance for the epidemic. After all, huge stores of vaccine had been produced. And all that would happen to those stores otherwise would be to reach their expiration dates. This was what our worldwide pandemic vaccine experts had been nattering about when the swine flu appeared. For example, from the state of Michigan Pandemic Vaccination Planning Guide:

"In the absence of a virus specifically matched to the pandemic virus, it is hoped that pre-pandemic H5N1 vaccine will have sufficient cross-reactivity to afford some protection to these groups.

The goal is to have sufficient vaccine for 20 million persons (at 2 doses per person). The trigger for using pre-pandemic vaccine has yet to be determined but would likely be evidence that an H5N1 virus had acquired the ability to spread efficiently from person to person. However, because the stockpiled vaccine will eventually lose potency, discussion has also occurred regarding possible administration to selected groups before the onset of a pandemic."

Given the above, how the experts would respond to swine flu was practically a foregone conclusion.

Naturally, they took their pandemic plans for bird flu (with mortality rates greater than the Black Plague) and forcibly fitted those plans to swine flu (arguably no more severe than seasonal flu). When swine flu first appeared, the Obama administration was new and there was no appointed HHS secretary, so the pandemic planners at DHS and DHHS likely had wide latitude to drive the program's direction.

That is why a huge vaccine campaign was undertaken, and why novel adjuvants were going to be used, without much question, even in the early planning, even in the United States. Here is a PPT presentation from Florida public health officials made in July, showing how H1N1 vaccines made by Sanofi-Aventis, CSL and GSK were all to be prepared for use with ASO3. The Novartis vaccine was to contain MF59. Probably Novartis, contracted for the biggest supply of swine flu vaccine, is "Company 3" described by Nicole Lurie in my last blog post.

Once swine flu is a thing of the past, watch to see if the idea of "prepandemic" bird flu vaccinations catch the fancy of our public health agencies. If the swine flu vaccine program is judged successful, bird flu vaccines may be next, with or without an epidemic. If there are serious safety or efficacy problems with swine flu vaccines, the bird flu vaccine will be shelved for awhile longer.

UPDATE: The Independent discusses costs and profits for swine flu vaccine and drug suppliers.

Vaccine Delays: limited info on the problems/Science Insider

From Jon Cohen and Martin Enserink, excerpts:

For proprietary reasons, Lurie would not name the delay issues at each manufacturer, but said “one company was just really overoptimistic” in its delivery predictions to HHS. Initially, all of the makers of inactivated vaccine had trouble with the “potency assay” used to ensure that 15 micrograms of influenza antigens are present in each dose. Once that was corrected, said Lurie, this company lost 20% to 35% of its antigen during the “recalibration.”

One [company] had a new production line to fill doses of vaccine into individual syringes. “Getting up the new production lines with prefilled syringes was really slow,” Lurie said. The third company had “major production problems” that Lurie said she could not describe in detail for proprietary reasons. Basically they had difficulty making “acceptable” vaccine that did not contain an immune booster called an adjuvant, which is used in several countries but not the United States.

In response to questions about safety, Frieden stressed at the press conference that these companies are using the same processes to make the novel H1N1 vaccine that they use each year to make 100 million or so doses of seasonal product. But if they have so much experience making the product, why so many snafus with the pandemic vaccine? “Almost every flu season, something goes wrong,” said Lurie, emphasizing that she was referring to manufacturing, not safety.

Germans Unhappy with Alternative Swine Flu Vaccine for Politicians/Spiegel

From Spiegel Online comes this story about how the German government and army ordered adjuvant-free vaccine for themselves, but adjuvanted Pandemrix (containing ASO3) for the rest of Germany. Excerpts follow:

Damage control is the name of the game in Berlin on Monday as politicians rush to deny that they are receiving a better, safer swine flu vaccine than ordinary Germans. The first of 50 million doses arrived in Germany on Monday. One might think that the arrival in Germany of the first of 50 million doses of swine flu vaccine on Monday might be cause for celebration. But with news breaking over the weekend that top government officials in Berlin will be injected with an alternative vaccine -- one widely seen as safer -- a debate about an alleged two-class medical system has erupted.

SPIEGEL over the weekend reported that Chancellor Angela Merkel, a number of her ministers and other government officials would receive a vaccine manufactured by the pharmaceutical company Baxter -- the same vaccine that the German military opted for, as was reported last week.

The controversy centers on an additive included in the vaccine manufactured by pharmaceutical giant GlaxoSmithKline. The additive includes an inactive strain of the entire flu virus as opposed to virus fragments. [Not accurate: see GSK's informational FAQ on Pandemrix, which contains ASO3. GSK tells us that ASO3 is proprietary and contains vitamin E, omitting information on its additional constituents. An inactive strain of the entire virus is not one of them, but squalene is included--Nass] Critics say the additive can increase the risk of side effects from the flu vaccine such as fevers and headaches.

Supporters counter that the additive is safe, and its use allows the drug manufacturer to quickly produce more doses of the vaccine. The SPIEGEL story mentioned that the GlaxoSmithKline vaccine, with the additive, has undergone more testing than the Baxter version.

An Interior Ministry spokesman told SPIEGEL that the Baxter vaccine had been ordered for all ministries and other agencies as well as for the employees of the Paul Ehrlich Institute, the authority responsible for approving vaccines.

The Green Party's health expert Biggi Bender said that the separate vaccines amount to "big risk for the people, little risk for the government. This type of second-class medicine cannot be allowed to exist in a democracy."

Leading physicians also complained about the planned vaccination. The head of the Institute for Hygiene and Public Health at the University of Bonn, Martin Exner, said: "The fact that politicians and top civil servants in ministries will be vaccinated with a vaccine other than the people is a terrible sign. Today politicians must take what they recommend."

The UK has seen an increase in cases in recent weeks. As a result, the country has purchased 60 million doses of Pandemrix.

The weekend scandal has drowned out a second debate which has been raging in recent weeks in the US and which has also found resonance here in Germany: whether such a massive vaccination program is necessary in the first place. Wolf-Dieter Ludwig, chairman of the Drug Commission of the German Medical Association, has called the planned vaccination campaign a "scandal." "The health authorities have fallen for a campaign from the pharmaceutical companies, who simply want to earn money with an alleged threat," he told SPIEGEL.

Adjuvanted vaccinations start Monday in Canada/ Globe and Mail

From the Globe and Mail:

Canada's vaccine uses an adjuvant, which consists of squalene (shark liver oil), DL-alpha-tocopherol (vitamin E) and polysorbate 80 (an emulsifier also used in ice cream). An adjuvant is a chemical product that boosts the immune response. There were claims that squalene, used in the anthrax vaccine, was to blame for Gulf War syndrome. But the evidence just wasn't there. Claims that mercury in vaccine causes autism have also been debunked.

Gulf War Syndrome probably resulted from exposures to a variety of noxious agents. Anthrax vaccine was one of them, and soldiers receiving anthrax vaccine who did not go to the Gulf have developed similar illnesses--but at a significantly lower rate. What role, if any. squalene played in Gulf War Syndrome has not been established one way or the other. Research supporting both sides has been published. But there is ample evidence that injecting squalene does cause illness in animals.

What I can say is that anthrax vaccine, with or without squalene, has made many people chronically ill. Early posts to this blog provide plenty of reading on problems with anthrax vaccine.

As far as mercury and autism, again, the jury is still out. Vaccinations with and without mercury have been followed by a descent into autism for some infants. Research both supporting and rejecting a role for mercury has been published. This is a nice review supporting a link between mercury and autism.

Emergency Use Authorization Issued for new, unlicensed antiviral drug Peramivir

From the Globe and Mail, Canada:  Peramivir first new antiviral in years.

This might be excellent:  it might be just what severely ill patients with swine flu need. 

However, before using this unlicensed drug, wouldn't you like to know what data exist on its safety and efficacy?  What do we know about iv zanamivir and oseltamvir safety and efficacy, for which there is sketchy information from case reports? (They are not licensed for iv use, but at least in other forms they  have undergone considerable testing.)

I'm glad that CDC and FDA are giving attention to treatment of severe swine flu cases.  What have they learned about the use of IVIG in swine flu patients with an IgG subclass deficit, said to be very helpful in a few Australian cases in pregnancy?   Where does this drug fit in to the swine flu armamentarium?  Hopefully, FDA will be collecting data on all cases in whom it is used.

New York Ends Flu Shot Mandate for Health Care Workers/ WSJ

Following issuance of a TRO last week, but possibly unrelated to it, NY State governor Patterson suspended the directive that all health care workers must receive influenza vaccinations.  The lawsuit will now be moot.

Virginia Officials: H1N1 may have peaked

I have been waiting for cases to peak and then go away.  Maybe that is what is happening in Virginia.  It is too bad no one is collecting seroprevalence data to learn how many people have already been affected and are now immune.

State health officials say that the H1N1 flu may be peaking in Virginia and could now start to decline.  Swine flu vaccine continues in short supply, emergency rooms are being flooded with sick and worried people, hospitals are restricting visitation, and school absenteeism is running well above normal in the state.

The proportion of visits to emergency rooms and urgent care centers attributed to suspected influenza reached 14.2 percent in Virginia this week, the state health commissioner said, a record high rate and double that of the last two flu seasons.

“We’re hoping that we may be approaching the top of the curve,” Dr. Karen Remley said Friday during a media teleconference.

After reaching 14 percent to 15 percent of emergency care visits, officials said, the potentially deadly H1N1 virus’s impact appears to be abating in states that saw an earlier onset of the disease than Virginia did....

Chinese trial of H1N1 vaccines/NEJM

A 2200 subject trial of Chinese H1N1 vaccines (developed from the same CDC virus as vaccines developed by western manufacturers) was published in the NEJM.  Four strengths of antigen were used in 4 age groups, with and without an aluminum phosphate (not a novel) adjuvant.

Of interest:  15 mcg of antigen was sufficient.  (This is the US dose being used.)  The aluminum adjuvant did not improve antibody levels.  (No aluminum adjuvant is included in the US vaccine.)  Children under 12 had the lowest antibody titres, but boosted well following a second dose.

The study only looked at antibody titres, and (like other reported studies) did not study how protective the vaccine was at preventing cases of swine influenza.

The placebo really was a placebo (phosphate buffered saline) unlike most western vaccine trials that use a different vaccine as the control.  With a true placebo, it became apparent that systemic reactions were 3-4 times higher in the vaccine group as compared to the placebo group.  True placebo groups need to be included in US vaccine trials, for without them the true reaction rates cannot be determined.

ASO3 and ASO4 adjuvants--my error

ASO3 is the GlaxoSmithKline adjuvant being used in some swine flu vaccines. It is not being used in the United States. It does contain squalene. It is being used in Canada and Europe. The presence of novel adjuvants in swine flu vaccines has become very controversial in some countries. WHO recommended that countries use the adjuvants to stretch the world supply of swine flu vaccines.

However...

ASO4 (not ASO3) is the GSK adjuvant used in Cervarix and Fendrix (a European Hepatitis B vaccine for patients with renal failure). It contains an aluminum salt and other ingredients. The package insert for Cervarix says it contains aluminum hydroxide, while the Fendrix insert says it contains aluminum phosphate, and refers to the adjuvant as ASO4-C. So it appears the ASO4 adjuvants in the two GSK vaccines are not identical.

Both ASO4 adjuvants contain Monophosphoryl lipid A (aka MPL or MPL-A). MPL has not been included in any previously-licensed vaccines in the US, and is considered a novel adjuvant. MPL is derived from bacterial lipopolysaccharide and is an immunomodulator. When MPL was used in experimental anthrax vaccines, squalene was included in the vaccines. However, neither the Cervarix nor Fendrix package inserts state that these vaccines include squalene. Therefore, my previous posts claiming those vaccines contained squalene are wrong. I will try to clarify the makeup of ASO4, and apologize for this error.

UPDATE: This article, whose authors work for Novartis and have shepherded MF59 along, clarifies the makeup and background of ASO4, ASO1, ASO2 and MF59.

Israel: H1N1 flu vaccine not suitable for pregnant women, sick kids/ Haaretz

Ha'aretz tells us that Israel only has adjuvanted vaccine available currently, and

The Health Ministry has decided to hold off on giving the swine flu vaccine to pregnant women and chronically ill children because vaccine stocks now in Israel contain a substance whose safety and effectiveness in pregnant women has not been fully substantiated. 

They will be offered unadjuvanted vaccine when it becomes available in November.

The Guillain-Barré syndrome and the 1992-1993 and 1993-1994 influenza vaccines/ NEJM

As I've said previously, before the 2009 swine flu came along, public health officials knew that vaccinations sometimes led to small increases in cases of GBS.  GBS cases (above baseline incidence levels) were not limited to the 1976 swine flu vaccine, but have occurred after other vaccines, although less commonly.

During the 1992-3 flu season, the incidence of GBS roughly doubled in flu vaccine recipients during the six week period following vaccination, according to a 1998 article in the New England Journal of Medicine by CDC and U Maryland authors:

BACKGROUND: The number of reports of influenza-vaccine-associated Guillain-Barré syndrome to the national Vaccine Adverse Event Reporting System increased from 37 in 1992-1993 to 74 in 1993-1994, arousing concern about a possible increase in vaccine-associated risk. METHODS: Patients given a diagnosis of the Guillain-Barré syndrome in the 1992-1993 and 1993-1994 influenza-vaccination seasons were identified in the hospital-discharge data bases of four states. Vaccination histories were obtained by telephone interviews during 1995-1996 and were confirmed by the vaccine providers. Disease with an onset within six weeks after vaccination was defined as vaccine-associated. Vaccine coverage in the population was measured through a random-digit-dialing telephone survey. RESULTS: We interviewed 180 of 273 adults with the Guillain-Barré syndrome; 15 declined to participate, and the remaining 78 could not be contacted. The vaccine providers confirmed influenza vaccination in the six weeks before the onset of Guillain-Barré syndrome for 19 patients. The relative risk of the Guillain-Barré syndrome associated with vaccination, adjusted for age, sex, and vaccine season, was 1.7 (95 percent confidence interval, 1.0 to 2.8; P=0.04). The adjusted relative risks were 2.0 for the 1992-1993 season (95 percent confidence interval, 1.0 to 4.3) and 1.5 for the 1993-1994 season (95 percent confidence interval, 0.8 to 2.9). In 9 of the 19 vaccine-associated cases, the onset was in the second week after vaccination, all between day 9 and day 12.
CONCLUSIONS: There was no increase in the risk of vaccine-associated Guillain-Barré syndrome from 1992-1993 to 1993-1994. For the two seasons combined, the adjusted relative risk of 1.7 suggests slightly more than one additional case of Guillain-Barré syndrome per million persons vaccinated against influenza.

In 2004, CDC scientists reported that, "Guillain-Barré syndrome remains the most frequent neurological condition reported after influenza vaccination to the Vaccine Adverse Events Reporting System (VAERS) since its inception in 1990."

A separate 1979 review of GBS cases found 532 people developed GBS shortly after swine flu vaccination. Canadian data questionably found a slight increase in GBS 2-7 weeks after flu vaccinations over many flu seasons.

From the Sept. 2009 Journal of Clinical Neuromuscular Diseases comes a study of GBS reports to VAERS.  The authors concluded, "Our results suggest that vaccines other than influenza vaccine can be associated with GBS."

CDC was concerned about the Menactra (meningitis) vaccine and GBS; see the MMWR on this subject. The WHO agreed that a small increased risk of GBS existed from meningitis vaccine.

Thus the link between GBS and vaccination has clearly been established, and acknowledged by CDC, despite obfuscation recently in the media.

Adjuvants and Thimerosal (aka Thiomersal)

Adjuvants stimulate increased, nonspecific immunity and are included in many "killed" vaccines. Until October 16, all adjuvants in licensed vaccines in the US were aluminum salts. They are included in tetanus, Hepatitis A and B, anthrax and other killed vaccines.

Thimerosal is a compound composed of 50% mercury which has been included in many killed vaccines to prevent growth of contaminating microorganisms. Due to concerns about its known toxicities, and the large doses of injected mercury that were administered when children received multiple vaccines on the same day, it was mostly (apart from flu vaccines) removed from US vaccines starting 10 years ago. Most currently available, killed vaccines only include about 5% of the amount of thimerosal they previously contained, or one microgram of mercury per dose. Some flu vaccines still contain 25 mcg mercury. Pandemrix contains 5 micrograms of thimerosal.

ASO4 is a more powerful adjuvant mixture than the currently used aluminum salts. Here is the package insert. The approval of the first novel adjuvant (containing MPL, not squalene) in a licensed US vaccine will open the floodgates to many new vaccines now in development, which contain ASO3, ASO4 and other powerful adjuvants.

Now that Cervarix is approved, the public can gain access to the data used to support licensure via Freedom of Information Act requests.

Cervarix: Novel (but NOT Squalene-containing) Adjuvant Approved in US

Despite data showing twice the rate of miscarriages in women who received Cervarix, FDA approved this new HPV vaccine from GlaxoSmithKline for the US market: the first-ever vaccine licensed in the US with a novel adjuvant, named ASO4.

According to a GSK press release, "In clinical trials, the most common side effects after vaccination with CERVARIX included pain, redness and swelling, fatigue, headache, joint and muscle aching, gastrointestinal symptoms and fever. Serious adverse events were generally comparable between the groups receiving CERVARIX and the control groups."

Recall that only 10 months ago FDA was trying to figure out how to study the safety of novel adjuvants. And FDA's chief scientist and then-head of the vaccine center (CBER) at FDA, Dr. Jesse Goodman, expressed significant safety concerns. What did FDA learn about analyzing adjuvant safety during the past ten months? What side effects may be attributable to this new vaccine additive? There is little unconflicted data in the medical literature to tell us.

Perhaps in fairness to Merck, FDA (on the same day it approved Cervarix) expanded the indications for Cervarix' competitor, Gardasil vaccine. Gardasil may now be used in boys to prevent sexually-transmitted genital warts, starting at age nine.

There exist a few reports of deaths and devastating neurological illnesses that developed in girls after receiving Gardasil vaccine. Contrary to what some have thought, Gardasil does not contain novel adjuvants. Cervarix does.

UPDATE: ASO4 contains MPL, not squalene, which is a different novel lipid adjuvant component.

Kids Under 5 Not at High Risk

Children under 5 years of age are at relatively low risk from Swine Flu, while teens are at relatively greater risk.  CDC finally acknowledged this on October 17, although CDC's data, published August 21, showed it then.

What's also surprising, Schuchat said, is that about half of the children who have died since the end of August were teenagers. Health officials thought younger children were more vulnerable.

I pointed this out (low risk in young children) on September 8 and September 11, based on CDC data from the MMWR publication, and noted then that the other G8 countries plus Mexico that met to discuss Swine Flu would not be recommending young children for vaccinations.

Furthermore,

Adding to the seriousness of the situation, manufacturing problems have delayed production of the H1N1 vaccine. Instead of reaching a goal of 40 million doses by the end of October, fewer than 30 million doses will be available, Dr. Anne Schuchat, director of the U.S. Centers for Disease Control and Prevention's National Center for Immunization and Respiratory Diseases, said.

But Schuchat is altering history here.  The September 15 NY Times reported that,

officials expect about 50 million doses of swine flu vaccine to reach government warehouses by Oct. 15, and another 20 million doses to be ready each week after that until 195 million is reached.

So by the end of October the US government will have only 30 million of a previously expected 90 million doses of swine flu vaccines, not 40 million as claimed by Schuchat.  Vaccine delays often reflect unforeseen issues with either safety or manufacturing standards.  It is unlikely the public will be informed of the specific reason(s) for the delay.

According to the Wall Street Journal, some people who hesitate getting vaccinated,

are concerned that flu shots can expose infants and toddlers to mercury, alleging a link between vaccines that contain thimerosal, a mercury-containing preservative, and autism.
Dr. Schuchat said Friday that while there is "no scientific basis" for those concerns, the CDC has "put in orders for quite a bit of thimerosal-free vaccine," so a choice can be available for pregnant women and young children. All H1N1 nasal spray vaccines are free of thimerosal, as well as some shots in single-dose syringes, she said. She said she couldn't specify how many of the 251 million doses the government has ordered will be free of the preservative, however.

Since Dr. Schuchat's group decided how many doses of the different Swine Flu vaccines to order, her ignorance on the number of doses expected to be available without mercury may be a clue that approval of these doses has been delayed due to manufacturing or safety problems.

Judge Halts Mandatory Flu Vaccines for Health Care Workers/ NYT

from the NY Times:

A temporary restraining order has been issued for mandatory vaccinations in New York state. In response,

"the State Department of Health vowed to fight the restraining order, saying that the authorities “have clear legal authority” to require vaccinations, and noted that state courts had upheld mandatory vaccinations of health care workers against rubella and tuberculosis. Justice McNamara scheduled a hearing for Oct. 30 on the three cases before him, involving the flu vaccine."

Interesting response, given that there is no effective tuberculosis vaccine, and rubella vaccines have been proven to cause arthritis and arthralgias in a significant minority of adult females who receive them, according to the Institute of Medicine.  Thus a good case can be made against mandating them.

Dr. Paul Offit Speaks/ NY Times

Dr. Paul Offit, head of pediatric infectious diseases at Children's Hospital, Philadelphia PA, and originator of a licensed Rotavirus vaccine recommended for all children, is an inveterate vaccine booster.  In his Oct 11 NYTimes Op-ed, he makes four claims about the new swine flu vaccine.  I'll briefly comment on each.

1.  The vaccine is safe because it is made with six decade-old technology.  IMHO, the lack of innovation could be considered good or bad.  The system of drug approval in the US favors drugs and vaccines remaining on the market even with known problems, given the high cost and prolonged period needed for new drug approval.  Why are vaccines still grown in hens' eggs, when so many eggs have bacterial contamination?  Why don't regulators provide some carrots (and/or sticks) to manufacturers in order to produce improved versions of vaccines?

The 1976 swine flu vaccine was also made with decades-old technology and caused Guillain Barre Syndrome.

2.  The vaccine has been tested in thousands.  The past tense here is wrong.  It is in the process of being tested, and few if any of the safety tests are completed.  We have very limited data, on only brief periods of observation for adverse reactions, and I have seen no data on safety in children or in pregnancy.

3.  Adjuvants are not being used.  Offit is correct:  no adjuvants are being used in swine flu vaccines for the US market.  Canada and many other nations have chosen to stretch their supply with novel adjuvants, whose safety is unknown but questionable, but the US decided otherwise.

4.  Thimerosal is safe.  25 micrograms of mercury per vaccine dose will be a component of most of the injectable US swine flu vaccine supply.  Mercury is a proven neurotoxin.  Whether and how much it may affect you, alone or in combination with other exposures, is not clear.  Still, I would not choose to have it injected into my body, given a choice.  The US is making mercury-free swine flu vaccine available for pregnant women and children, some of whom will receive two vaccine doses.

German Army ordered thimerosal-free, adjuvant-free swine flu vaccine for soldiers (Civilians get the vaccine with these additives)

From The Local, an English-language German newspaper, comes this report.  Interesting.

My powerpoint presentation to NVIC conference

The presentation discussed the legal framework for scientific misconduct, other questionable practices in science that are not legally prohibited, and how such practices were employed to create a body of literature that falsely proclaims anthrax vaccine's safety.  Also discussed was the role of anthrax vaccine in bioterrorism, its history since 1970, and the new laws regulating medical products for bioterrorism.  The PREP Act was invoked for anthrax vaccine last year and for all US swine flu vaccines in 2009, creating an entirely new regime for dealing with vaccine injuries, the Countermeasure Injury Compensation Program.  This compensation program prohibits access to the legal system for injuries from "covered countermeasures" such as swine flu vaccine.  The Emergency Use Authorization was invoked by the HHS Secretary in 2005, after the courts lifted the anthrax vaccine license, as a legal means to enable mass military use of an unlicensed product.  It was considered for use if US swine flu vaccines included novel adjuvants.

U.S. school swine flu event shows vaccine challenge/ Reuters

From Reuters:

A U.S. government media event to promote H1N1 school vaccinations on Friday included VIPs, cute kids and a phalanx of television cameras -- but only one in five children at the school had proper parental consent to get immunized. . .

But the small numbers also underscored the challenge facing the U.S. government's $6.4 billion immunization effort which involves the widespread use of schools as vaccine clinics for the first time in a generation.

H1N1 poses a greater danger of severe illness and death for children and young people than seasonal flu, which is particularly dangerous for the elderly.

Another [problem] was that the only vaccine on offer was AstraZeneca unit MedImmune's nasal spray, which is unsuitable for children with underlying conditions such as asthma. [It historically is less effective than injections, and effectiveness of flu vaccines in children is even more uncertain than in adults, but since the spray is available first, we are giving it to our children before there is even adequate data in adults.]

Loyalty Oaths: Still Going Strong

Senator Joe McCarthy has been dead over 50 years, but the loyalty oaths that became notorious after his fall are alive and well in America today.

Loyalty oaths? Perhaps you haven't seen any.  But perhaps you've simply missed what was right before your eyes.

There are different kinds of loyalty oaths.  Some require you to publicly disavow what millions of Americans believe to be true.

Van Jones, green jobs advisor to the Obama administration, signed a 2004 petition calling for congressional hearings - as well as an investigation by the New York Attorney General - into "evidence that suggests high-level government officials may have deliberately allowed the September 11th attacks to occur."  It didn't matter that John Farmer, dean of Rutgers Law School and former counsel of the 9/11 Commission published a book, The Ground Truth: The Untold Story of America Under Attack on 9/11, the same month Jones resigned.  The book concluded, according to Publishers Weekly, "the official version of events was almost entirely, and inexplicably, untrue."  Jones still had to recant and resign.  The loyalty oath requires that you swallow the blue pill and accept the official version.

Bruce Ivins overdosed on tylenol after extensive browbeating, surveillance and harrassment of family members.  Now the National Academy of Sciences is spending more government money to answer the wrong questions about the FBI's anthrax letters case ... a small price to pay, to give the NAS imprimatur to the FBI's failed investigation into the letters.  Don't ask how and by whom Ivins was set up, and before him, Hatfill, Assaad and Mikesell.  Don't ask about the fact there is no evidence to support a conviction.  Don't ask who crafted and supervised this most bumbling of FBI investigations.  Don't ask how so many complex assassinations of political leaders in this country have been carried out by lone nuts.  Take the loyalty oath and agree that a "lone nut" sent the letters.

Do you know someone with a child that was perfectly normal, then over a couple of weeks faded into autism after a vaccine?  Fuggedaboudit.  If you are a medical professional you can question the safety of drugs, but you better not question the safety of vaccines.  Just because the vaccine package inserts list adverse events doesn't mean they were caused by vaccines.  You want smallpox coming back?  Keep asking questions, and your career may just head south.  Take the loyalty oath instead:  it's a lot safer.

Got lyme disease?  It went away after a 3 or 4 week treatment, right?  Oh, it didn't?  That means you must have something else.

You say your symptoms are the same as when it started?  Are you sure you're not depressed?  You may think you have lyme disease, but you don't.  You say lyme bacteria take at least 12-24 hours to divide, unlike other bacteria that can divide in 20 minutes?  Lyme bacteria live inside cells where antibiotics don't achieve high levels? Are you trying to tell me that tuberculosis bacteria take the same amount of time to divide, and they get treated for 9-12 months?

What are you, some kind of armchair microbiologist?  Get a grip.  Go see a pain doctor, and get some therapy.  No doctor will treat you long-term anyway... didn't you hear that over 40 doctors who did offer prolonged treatments for lyme had the states go after their licenses?  The docs learned to take the loyalty oath:  now it's your turn.  Where's that blue pill?

UPDATE:  UK doctors and nurses also have to take a biologic loyalty oath:  swine flu vaccine.  According to the Guardian:

The Department of Health has ordered NHS bosses across England to ensure that frontline staff get immunised against swine flu amid growing signs that many doctors and nurses intend to shun the vaccine.  Leading DH figures including Sir Liam Donaldson, the chief medical officer, have written to them six times in the last five weeks stressing the need for action before the second wave of the pandemic causes major problems... hospital chief executives have told the Guardian that they expect as few as 10%-20% of their staff to get vaccinated and cannot fulfill the DH's demands because the jabs, which are due to begin within days, are entirely voluntary.

Why do I call this a loyalty oath?  Because medical professionals who understand perfectly well there is no evidence the vaccine is safe or reasonably effective are being pressured to ignore their professional judgment and accept a potentially risky medical intervention.  Presumably the goal is to set an example for the rest of the public.

Is the point simply to demonstrate the government's wisdom in embarking on the world's largest (and most unnecessary) vaccination program in history?  The UK traditionally has not mandated vaccinations.

Swine Flu: To Vaccinate or Not?

French physician and pharmacoepidemiologist Marc Girard has written a valuable piece on swine flu vaccines, their risk assessment and their rushed approval, contrasting this with what should ordinarily take place before a drug or vaccine enters the market.

76 total US child deaths from swine flu in 2009/WaPo

From the Washington Post:

According to the Post, 19 of the 76 deaths occurred during the past week. But according to CDC, the 19 deaths actually occurred between July 19 and October 3.  They were reported last week.

So far, approximately one in a million US children have died from swine flu-associated causes.  But only 23 or less were entirely healthy:

While most of the children who have died have had other health problems that made them particularly vulnerable, such as asthma, muscular dystrophy and cerebral palsy, 20 to 30 percent were otherwise healthy, Schuchat said.

Therefore, one in ten deaths occurred in children under 18 years, who comprise about 20% of the population.  At least 28 pregnant women have died, and at least 800 total Americans. Update 10/16:  I mistakenly used the total number of deaths in the world earlier.  Current US deaths are 800-1000.

Only 1 in 30 deaths occurred in pregnant women.  Which indicates that pregnant women are at a bit greater risk of death than anyone else.  Still, why are we vaccinating women during pregnancy when not a single trial of safety in pregnancy has been reported?  Protecting the fetus has to be given due weight as well, when calculating risk and benefit during pregnancy.

What Pandemic?

According to the CDC, US deaths from influenza and pneumonia were significantly greater in 2008 than  they have been in 2009, despite all the hoopla about pandemic swine influenza.  Here is CDC's own data.  CDC also tells us, on the same website, that 60 children have died from swine flu in the US in the past year, while 68 children died from seasonal flu in the past year in the US. 

Why Am I Concerned about Safety of Swine Flu Vaccines?

My friend Mark Crispin Miller has urged me to be more specific about why I am concerned about the safety of swine flu vaccines in the US. In a nutshell:

1. Newness

I am always concerned about new drugs and vaccines. A former FDA Commissioner, Dr. Jane Henney, once said she did not use drugs during the first year they were on the market, and advised others to likewise avoid them. The reason is that many drugs and vaccines have caused serious side effects that were not picked up, or not considered enough of a concern, during initial clinical trials. Rotashield vaccine is a good example: intussusception (causing bowel obstruction) did occur but was overlooked in prelicensure trials because it was judged unrelated to the vaccine, and a million babies received the vaccine before it was taken off the market in 1999. Rotashield caused 22 times the expected rate of intussusception in infants, causing much more harm than good... but was marketed for 11 months. Because this was the first time intussusception was ever connected to a vaccine, it wasn't considered plausible that a vaccine could cause this until after 1,000,000 children were exposed.

Pre-licensure trials typically involve only one to several thousand subjects for short periods of time.

2. The currently available evidence is thin and inadequately collected

There are few published studies of swine flu vaccine. The Greenberg et al. study from Australia (Response after one dose of a monovalent influenza A H1N1 2009 vaccine--preliminary report; NEJM 2009; epub Sept. 10) is a relatively high quality study. How was vaccine safety evaluated? By using a diary card for 7 days post-vaccination. The 240 subjects returned on day 21 for a blood draw, and presumably some data were collected then, but it is not clear from the published report what safety information was obtained after 7 days. Local symptoms like a sore arm were reported by 46% of subjects, and systemic symptoms such as headache, muscle aches or malaise were reported by 45%. Subjects were healthy adults aged 18-64.

The authors stated, "No deaths, serious adverse events or adverse events of special interest were reported." The investigators did specifically query subjects about several neurologic and immunologic events, including Guillain Barre Syndrome. However, it is unclear how actively other adverse events were sought, if at all, after the initial seven days post-vaccination.

The authors acknowledge that, "The full safety profile of the H1N1 vaccine has not yet been elucidated. Population-based postlicensure surveillance will be required for all H1N1 vaccines, especially to assess rare outcomes, such as the Guillain-Barre Syndrome." And they point out that they studied a population of healthy adults, and "trials need to be conducted in other populations that may have different responses to the vaccine, such as the elderly, children, and those with impaired immunity."

What further concerns me are the later side effects that will not be collected, or not attributed to the vaccine due to lack of "biological plausibility." Since there do not exist reliable scientific criteria for assigning causality to vaccine adverse events, those the vaccine causes are likely to be dismissed as coincidental. Compounding this problem, the brief periods of active surveillance are insufficient to identify later reactions. When it takes 10-14 days to achieve peak antibody levels, a week of active surveillance for side effects is clearly inadequate.

3. The Liability Waiver... blanket immunity in the absence of willful misconduct

As I've noted previously, swine flu vaccine manufacturers can only be sued for damages if they are guilty of willful misconduct. As long as they don't know about safety problems, they cannot be held liable for them. This thoughtless language in the Public Readiness and Emergency Preparedness Act, which regulates pandemic vaccines, may induce manufacturers to perform minimal safety testing in order to avoid potential liability. Don't you think corporate attorneys have so advised their clients?

4. When the program isn't transparent, the result is lack of trust.

I expect the government, which is supplying free swine flu vaccines, to advise recipients honestly about them. Live flu vaccines have very low efficacy in adults, compared to injected subunit vaccines. How attractive would a nasal vaccine that was only 29% effective at preventing influenza be to you, when the injected vaccine had 72% efficacy? Yet this is what Monto et al. recently reported in the NEJM about last year's seasonal vaccine. It makes you wonder why live flu vaccines are even licensed for adults. And how good are they in children? Better--but the data are limited.

Some hospitals are refusing live nasal vaccines for employees. That is wise: they are concerned the live viruses could be transmitted to patients, especially those with impaired immunity. They should also be concerned about efficacy (29% isn't very good) of live nasal vaccine. Why didn't government tell the public about these concerns? Why didn’t government tell the public it issued a liability waiver to the manufacturers?

Schools offering these vaccines don't seem to be aware of potential problems such as vaccine virus transmission to immune-compromised students.

5. Benefit and risk should be compared

Yes, there are serious swine flu illnesses and deaths in a young, healthy population. But how frequent are they? How good is the vaccine at protecting against them? The very best flu vaccines are about 70% protective against catching the disease, which is the measure you are interested in. Most studies measure the rise in antibody levels, which may not reflect actual protection.

During 4 weeks in September there were 182 confirmed influenza deaths in the US. Though not a small number, it is not a big number either compared to seasonal flu. Admittedly incomplete, WHO has reports of just 4100 deaths worldwide since the pandemic began. There have been 60 deaths in US children related to swine flu since the pandemic began.

Cities (like Boston and New York) that had a lot of swine flu cases in the spring are having few now, suggesting a large enough number of people (perhaps 50% or more to induce this effect) had subclinical infections, generating herd immunity. It is likely many will be vaccinated who are already immune. In the Australian trial 31.7% of vaccine recipients had antibodies against swine flu before they were vaccinated, even though they had no symptoms of disease. The effect of preexisting antibody spuriously raises vaccine efficacy statistics in some trials, and reduces the need for vaccine.

If you have a neuromuscular disorder or lung disorder, you are at higher risk of a serious outcome from flu. Thus your benefit from vaccination is greater.

Vaccination was once intended for only the most serious illnesses. Doctors knew some children would develop encephalopathies (brain injuries) as a result of vaccination, but the risk was worth the benefit. Over time, and as the profits from vaccines have risen, "mission-creep" has led to increasing numbers of vaccines for less serious illness, even moving vaccine development into areas of non-infectious diseases like cancer. During this process, appreciation of vaccine risks got marginalized.

The benefit of vaccination should be balanced against the risk, but as yet we don't know the risk. I do my best to balance the known and potential risks and benefits as I advise people regarding vaccination, and I hope readers of this blog do also. Vaccination shouldn't be a “one size fits all” intervention.